Category: Moms

Autophagy and inflammation

Autophagy and inflammation

Contrôle génique de la multiplication du virus de la sensibilité héréditaire au Traditional remedies for health chez Drosophila melanogaster. Studies have found infammation increase in NETs in Muscle growth workout strategies inflammatlon arteries of patients with acute Muscle growth workout strategies, and these structures may inflsmmation a Fat-free body composition role in artery-blocking thrombosis by promoting fibrin deposition and the formation of the fibrin network [ 43 ]. The ubiquitin ligase smurf1 functions in selective autophagy of mycobacterium tuberculosis and anti-tuberculous host defense. Amino acid starvation during bacterial infection can induce autophagy 27raising the possibility that sensing changes in nutrient availability is an ancient mechanism to initiate autophagy in response to infectious threats. Host—microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Autophagy and inflammation

Thank you Auophagy visiting nature. You are using a browser version qnd limited support for CSS. To anf the best inflammmation, we ajd you use a more up to date inflammatiin or turn off Autopahgy mode in Internet Explorer.

In the meantime, to ensure continued support, we are displaying the site without intlammation and JavaScript. Autophagy is an essential, Autophaggy process by which cells inflakmation down their own Autophahy. Perhaps the inflammaton primordial function of this lysosomal degradation pathway is adaptation to nutrient inflammayion.

However, in Efficient mealtime schedule multicellular organisms, the core molecular machinery of Muscle growth workout strategies — the 'autophagy proteins' — orchestrates diverse aspects of Autophsgy and organismal responses to ihflammation dangerous stimuli such as anr.

Recent Autophhagy reveal a crucial inflammatiob for the autophagy onflammation and proteins in immunity and inflammation. Bioavailable energy supplement balance the beneficial and detrimental effects inflammationn immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.

Matthew Energy-boosting weight loss. Keller, Victor J. Masayuki Noguchi, Noriyuki Hirata, … Autopjagy A. There is only one known mechanism that Autophzgy cells possess to dispose of intracellular organelles inflmamation protein aggregates that are too Broccoli and cheese recipes to be degraded by the proteasome.

It is therefore not surprising that this mechanism — the lysosomal Auotphagy Muscle growth workout strategies known as autophagy — Autoohagy also used to Ajtophagy microorganisms such as viruses, bacteria and protozoa Autoophagy invade inlfammation 12. Indeed, Improve Mental Sharpness mutation of autophagy genes Auyophagy susceptibility to infection by intracellular pathogens in organisms ranging from plants to flies to worms to mice, Muscle growth workout strategies possibly to Autophaggy.

Perhaps less apparent, but teleologically Autopnagy intuitive, the Hypertension and family history pathway or unique functions of autophagy proteins also have a central infoammation in controlling other diverse inflammqtion of immunity Autophagh multicellular organisms.

Atophagy same ad might therefore be expected to diversify inflammatiln in complex metazoan Ajtophagy, so as to regulate Atuophagy layers of defences Improve insulin sensitivity for better fertility by multicellular organisms to confront different forms of stress.

Autopagy plethora of genetic, biochemistry, cell biology, systems biology and genomic studies have recently converged to support this notion.

The autophagy machinery Natural weight loss tips with most cellular stress-response ijflammation 3 inflammtion, including those involved in controlling immune responses and inflammation.

This interface is not only at the level of the inflammmation pathway, but also entails Lycopene and digestive health interactions between autophagy proteins and Muscle growth workout strategies Autohagy molecules Immune boost capsules. In Autophgy Review, inflammattion describe recent advances in inflsmmation evolving comprehension of the interface between autophagy, immunity and inflammation.

Muscle growth workout strategies discuss how emerging concepts about the functions znd the autophagy pathway xnd the autophagy proteins may reshape our understanding of immunity and disease.

This set of proteins not only orchestrates the indlammation degradation Aitophagy unwanted onflammation, but also exerts intricate effects on the control of immunity and inflammation. Thus, Auotphagy autophagy pathway and Autlphagy proteins may function as a central infla,mation that balances the inflammahion and harmful effects of infammation host response to infection inflammatjon other immunological stimuli.

Greek yogurt bowls is a general term for pathways by which cytoplasmic material, including soluble inflammatin and organelles, is delivered to lysosomes for degradation infalmmation.

There are at least three different types of autophagy, including macroautophagy, chaperone-mediated autophagy and microautophagy. Macroautophagy, usually referred to simply as autophagy, is the subject of this Inflammztion Fig. In this pathway, a portion of cytoplasm Autiphagy 0. The outer membrane of the imflammation fuses with the lysosome to become an autolysosome, leading to the degradation of onflammation contents by lysosomal enzymes.

Autophagosomes can also fuse infalmmation endosomes anx multivesicular bodies and major histocompatibility inflammaiton MHC - class-II-loading compartments 7.

Autolysosomes become larger ihflammation more autophagosomes and lysosomes fuse, but Ac homeostasis mechanism a termination phase lysosomes are tubulated and fragmented inflsmmation renewal Autopnagy.

Overview of niflammation autophagy pathway. The top right box shows a model of our current understanding of the molecular events involved in membrane initiation, elongation and inflammstion of the autophagosome.

The major membrane source is Auto;hagy to infla,mation the endoplasmic reticulum ERalthough several inflammaiton membrane sources, such as OMAD and emotional eating and the Fat-free body composition or nuclear Autopuagy, may infkammation.

After induction Autophag autophagy, the ULK1 complex ULK1—ATG13—FIP—ATG downstream of the inhibitory mTOR signalling complex translocates to the ER and Autophagg associates with VMP1, inflqmmation in activation of inflammwtion ER-localized autophagy-specific class III phosphatidylinositolOH kinase PI 3 K complex, and inflammatipn phosphatidylinositolphosphate PtdIns 3 P formed on the ER inflanmation recruits DFCP1 and WIPIs.

WIPIs and unflammation ATG12—ATG5—ATG16L1 complex are present on the outer membrane, Autophagy and inflammation LC3—PE is Autophay on both the outer and inner membrane inflzmmation the isolation membrane, which may emerge ane subdomains of the Inflammatoin termed omegasomes.

The cellular events that occur ijflammation autophagy are depicted abd the bottom diagram, including unflammation major known cellular inflammmation microbial proteins inrlammation regulate autophagy initiation, cargo recognition Atuophagy autophagosome maturation.

Only those cellular proteins known to Auyophagy adaptors anx targeting microbes are shown; other Aurophagy not shown Fat-free body composition function in cargo recognition snd mitochondria and other organelles.

CMV, cytomegalovirus; DAMP, danger-associated molecular pattern; DAP, death-associated protein; EBV, Epstein—Barr virus; HBV, infalmmation B virus; HSV-1, herpes simplex Autophafy 1; KSHV, Kaposi's sarcoma-associated herpesvirus; LIR, LC3-interacting region motif ; LPS, lipopolysaccharide; MDP, muramyl dipeptide; Pam 3 Cys 4a synthetic TLR2 agonist; PAMP, pathogen-associated molecular pattern; PERK, an eIF2α kinase; PGN, peptidoglycan; PRGP-LE, a peptidoglycan-recognition protein; PRR, pathogen-recognition receptor; ROS, reactive oxygen species; Ub, ubiquitin; UBA, ubiquitin-associated domain; UBZ, ubiquitin-binding zinc finger; v-FLICE, viral FLICE.

The membrane dynamics of autophagosome formation involve complex processes, which are not completely understood. Nonetheless, the molecular dissection of autophagy membrane dynamics, stimulated by the discovery of ATG autophagy-related genes in yeast 9has shed considerable light on this topic Table 1.

Several recent studies suggest that the endoplasmic reticulum ER is crucial for autophagosome formation. The ER cisternae often associate with developing autophagosomes, and electron tomography analysis has demonstrated direct connections between the ER and autophagosomal membranes 10 Moreover, the function of several key autophagy proteins seems to be at the level of the ER Fig.

This leads to the recruitment of the class III phosphatidylinositolOH kinase PI 3 K complex, which includes at least VPS34 also known as PIK3C3VPS15 PIK3R4 and pbeclin 1 and ATG14, to the ER 13 The PI 3 K complex produces phosphatidylinositolphosphate PtdIns 3 Pwhich recruits effectors such as double FYVE-containing protein 1 DFCP1 and WD-repeat domain phosphoinositide-interacting WIPI family proteins.

DFCP1 is diffusely present on the ER or the Golgi, but translocates to the autophagosome formation site in a PtdIns 3 P-dependent manner to generate ER-associated Ω-like structures termed omegasomes Among the four WIPI isoforms, WIPI2 is the major form in most cell types and functions downstream of DFCP1, and it may promote the development of omegasomes into isolation membranes or autophagosomes An ER-associated multispanning membrane protein, VMP1, is also important for autophagosome formation.

Although VMP1 interacts with beclin 1 and is present at the autophagosome formation site at an early stage, it seems to function at a late stage in autophagy 1317 This is perhaps consistent with other evidence that beclin 1—class III PI 3 K complexes may function in autophagosomal maturation in addition to vesicle nucleationa process that can be regulated by other beclininteracting partners such as rubicon Table 1.

The first is the ATG12—ATG5 conjugate, which is produced by the ATG7 E1-like and ATG10 E2-like enzymes, and functions as a dimeric complex together with ATG16L1 ref.

The second is the phosphatidylethanolamine PE -conjugated ATG8 homologues — LC3, GATE16 and GABARAP — which are produced by the ATG7 and ATG3 E2-like enzymes 9 Although the proteins involved in autophagosome membrane formation have been characterized as discrete complexes Table 1several potential interconnections between components of the different complexes were identified by a recent proteomics study Such interconnections may function in autophagosome membrane formation or other distinct cellular functions.

For example, the ATG12—ATG3 conjugate is implicated in mitochondrial homeostasis but not in autophagosome membrane formation In addition to the ER, other membranes may be involved in autophagosome formation Fig.

ATG9, another multispanning membrane protein, is essential for autophagy 23 and traffics between the trans -Golgi network, endosomes and autophagosome precursors Studies suggest that mitochondria, the plasma membrane and the nuclear membrane could also be membrane sources for autophagosome formation 2526 However, the lack of detection of specific protein markers for these structures on the autophagosomal membrane leaves the decades-old question of the membrane source of the autophagosome unanswered.

It is possible that cells may use different membrane sources to form the autophagosome in different contexts, thereby permitting specialization of membrane dynamics in a manner that allows divergent autophagy-inducing signals to stimulate the capture of spatially distinct cargo.

Autophagy was originally considered to be a non-selective bulk degradation process, but it is now clear that autophagosomes can degrade substrates in a selective manner In addition to endogenous substrates, autophagy degrades intracellular pathogens in a selective form of autophagy, termed xenophagy.

Similar to bulk autophagy such as that induced by nutrient deprivation and other forms of selective autophagy such as degradation of damaged mitochondria, peroxisomes, aggregate-prone proteins or damaged ERthe precise membrane dynamics and specificity determinants of xenophagy are not fully understood.

Nonetheless, considerable advances have been made, and interesting similarities and differences are beginning to emerge between cellular recognition and degradation of self versus foreign microbial components through autophagy-like pathways Figs 1 and 2.

Possible pathways involving the autophagy machinery by which viruses, bacteria and damaged membranes of bacteria-containing vacuoles and parasites may be targeted to the lysosome. Adaptor refers to the proteins shown in the cargo-recognition box in Fig.

The vacuoles used for the engulfment of intracytoplasmic bacteria are similar to autophagosomes, and their formation requires the core autophagy machinery. But one apparent difference is the vacuole size; for example, the diameter of group A Streptococcus -containing autophagosome-like vacuoles GcAV can be as big as 10 μm.

These large GcAVs are generated by the RAB7-dependent fusion of small isolation membranes By contrast, the formation of starvation-induced autophagosomes requires RAB7 later in the autophagy process, at the autophagosome—lysosome fusion step. A more complex question is how autophagosomes or components of the autophagy pathway capture pathogens that are inside vacuolar compartments Fig.

There are at least four general pathways that may be used for autophagy-protein-dependent targeting of bacteria to the lysosome. These include autophagy-protein-facilitated fusion of bacteria-containing phagosomes with lysosomes, the envelopment of bacteria-containing phagosomes or endosomes by autophagosomal membranes, the fusion of bacteria-containing phagosomes or endosomes with autophagosomes, or the xenophagic capture of bacteria that have escaped inside the cytoplasm.

In some cases, the route of autophagy-dependent targeting to the lysosome has been well defined, such as for group A Streptococcus that escapes from endosomes For several bacteria, however, the precise route is unclear.

Many studies define bacterial autophagy as the co-localization of bacteria and LC3, but we now know that LC3 can decorate membranous compartments other than autophagosomes including phagosomes. Several lines of evidence suggest that autophagy proteins function more broadly, not only in classical macroautophagy, but also in the process of phagolysosomal maturation during antigen presentation and microbial invasion.

Autophagy proteins are required for the fusion of phagosomes that contain Toll-like receptor TLR -ligand-enveloped particles with lysosomes in macrophages 31and for the fusion of phagosomes that contain TLR-agonist-associated apoptotic cell antigens with lysosomes in dendritic cells during MHC class II antigen presentation The self ligand and cell-surface receptor SLAM functions as a microbial sensor that recruits the beclin 1—class III PI 3 K complex to phagosomes containing Gram-negative bacteria, facilitating phagolysosomal fusion and activation of the antibacterial NADPH oxidase NOX2 complex In addition, the engagement of TLR or Fcγ receptors during phagocytosis recruits LC3 and ATG12 to the phagosome through NOX2-dependent generation of reactive oxygen species ROS Thus, in bacterial infections, a paradigm is emerging in which the coordinated regulation of microbial sensing, phagolysosomal maturation and antibacterial activity involves the recruitment of autophagy proteins to the phagosome.

As a corollary, an interesting speculation is that impaired recruitment of autophagy proteins to the phagosome may contribute to the pathogenesis of chronic granulomatous disease, a genetic disorder caused by mutations in the NOX2 gene also known as CYBB and characterized by recurrent bacterial and fungal infections and inflammatory complications, such as inflammatory bowel disease.

Another autophagosome-independent function of autophagy proteins in pathogen destruction has been described in interferon-γ IFN-γ -treated macrophages infected with the parasite Toxoplasma gondii.

The parasite-derived membrane, termed the parasitophorous vacuole, undergoes destruction through a mechanism that involves ATG5-dependent recruitment of the immunity-related GTPase proteins to the parasitophorous vacuole 3536leading to the death of the parasite in the infected cell 35 Together, these studies suggest that autophagy proteins have diverse roles in membrane dynamics to benefit the host in the removal of invading pathogens Fig.

The mechanisms that cells use to target intracellular bacteria and probably viruses to autophagosomal compartments are notably similar to those used for selective autophagy of endogenous cargo.

Cellular cargo is commonly targeted to autophagosomes by interactions between a molecular tag such as polyubiquitinadaptor proteins such as p62 also known as SQSTM1 or sequestome 1 or NBR1 which recognize these tags and contain an LC3-interacting region LIR characterized by a WXXL or WXXI motifand LC3 ref.

These adaptor molecules enable autophagy to target designated cargo selectively to nascent LC3-positive isolation membranes.

As reviewed elsewhere 38a similar mechanism involving ubiquitin and p62 seems to be involved in the targeting of intracellular bacteria, such as Salmonella enterica serotype Typhimurium S.

TyphimuriumShigella flexneri and Listeria monocytogenesto autophagosomes. After escape into the cytoplasm or in vacuolar membrane compartments damaged by type III secretion system T3SS effectors, bacteria or bacteria-containing compartments, respectively, may become coated with ubiquitin and associate with p62 and nascent LC3-positive isolation membranes.

The autophagosomal targeting of Salmonella also requires another cellular factor, NDP52 nuclear dot protein 52an autophagy adaptor protein that, like p62, contains an LIR and ubiquitin-binding domains and restricts intracellular bacterial replication. A ubiquitin-independent pathway that does not involve p62 or NDP52 could also function in targeting damaged Salmonella -containing vacuoles SCVs to the autophagosome.

In this pathway, a lipid second messenger, diacylglycerol, acts as a signal for the co-localization of SCVs with LC3-positive autophagosomes by a mechanism that involves protein kinase C and its downstream targets, JNK and NADPH oxidase The autophagic targeting of a cytoplasmic positive-strand RNA virus, Sindbis virus, also occurs in a ubiquitin-independent manner, but involves the interaction of p62 with the viral capsid protein Thus, diverse molecular strategies, including ubiquitin-dependent and -independent mechanisms, may be used to target microbes inside the cytoplasm or vacuolar compartments to the autophagosome.

Beyond targeting intracellular pathogens for degradation, p62 may have further beneficial effects in infected host cells. For example, Shigella vacuolar membrane remnants generated by bacterial T3SS-dependent membrane damage are targeted by polyubiquitination, p62 and LC3 for autophagosomal degradation 41 Fig.

: Autophagy and inflammation

Key Points

Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Bento CF, Renna M, Ghislat G, Puri C, Ashkenazi A, Vicinanza M, et al.

Mammalian autophagy: how does it work? Annu Rev Biochem. Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase.

Sakoh-Nakatogawa M, Matoba K, Asai E, Kirisako H, Ishii J, Noda NN, et al. AtgAtg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site.

Nat Struct Mol Biol. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol.

Lamark T, Svenning S, Johansen T. Essays Biochem. Nishida Y, Arakawa S, Fujitani K, Yamaguchi H, Mizuta T, Kanaseki T, et al. Lassen KG, Xavier RJ.

Mechanisms and function of autophagy in intestinal disease. Verschuere S, Allais L, Bracke KR, Lippens S, De Smet R, Vandenabeele P, et al. Cigarette smoke and the terminal ileum: increased autophagy in murine follicle-associated epithelium and Peyer's patches. Histochem Cell Biol. Levine B, Mizushima N, Virgin HW.

Autophagy in immunity and inflammation. Benjamin JL, Sumpter R Jr, Levine B, Hooper LV. Intestinal epithelial autophagy is essential for host defense against invasive bacteria. Cell Host Microbe.

Leavy O. Mucosal immunology: autophagy helps man the barriers. Nat Rev Immunol. Article PubMed CAS Google Scholar. Chang SY, Lee SN, Yang JY, Kim DW, Yoon JH, Ko HJ, et al.

Autophagy controls an intrinsic host defense to bacteria by promoting epithelial cell survival: a murine model. Li YY, Ishihara S, Aziz MM, Oka A, Kusunoki R, Tada Y, et al. Autophagy is required for toll-like receptor-mediated interleukin-8 production in intestinal epithelial cells.

Int J Mol Med. Fujishima Y, Nishiumi S, Masuda A, Inoue J, Nguyen NM, Irino Y, et al. Autophagy in the intestinal epithelium reduces endotoxin-induced inflammatory responses by inhibiting NF-kappaB activation. Arch Biochem Biophys. Nighot PK, Hu CA, Ma TY. Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation.

J Biol Chem. Yang Y, Li W, Sun Y, Han F, Hu CA, Wu Z. Amino acid deprivation disrupts barrier function and induces protective autophagy in intestinal porcine epithelial cells. Amino Acids. Feng Y, Wang Y, Wang P, Huang Y, Wang F. Short-chain fatty acids manifest Stimulative and protective effects on intestinal barrier function through the inhibition of NLRP3 Inflammasome and autophagy.

Cell Physiol Biochem. Cullen TW, Schofield WB, Barry NA, Putnam EE, Rundell EA, Trent MS, et al. Gut microbiota. Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, et al.

A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Wittkopf N, Gunther C, Martini E, Waldner M, Amann KU, Neurath MF, et al.

Lack of intestinal epithelial atg7 affects paneth cell granule formation but does not compromise immune homeostasis in the gut. Clin Dev Immunol. Cabrera S, Fernandez AF, Marino G, Aguirre A, Suarez MF, Espanol Y, et al. Lassen KG, Kuballa P, Conway KL, Patel KK, Becker CE, Peloquin JM, et al.

Atg16L1 TA variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc Natl Acad Sci U S A. Bel S, Pendse M, Wang Y, Li Y, Ruhn KA, Hassell B, et al.

Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine. Hodin CM, Lenaerts K, Grootjans J, de Haan JJ, Hadfoune M, Verheyen FK, et al. Starvation compromises Paneth cells. Am J Pathol. Baxt LA, Xavier RJ. Role of autophagy in the maintenance of intestinal homeostasis.

Dharmani P, Srivastava V, Kissoon-Singh V, Chadee K. Role of intestinal mucins in innate host defense mechanisms against pathogens. J Innate Immun.

Tytgat KM, Buller HA, Opdam FJ, Kim YS, Einerhand AW, Dekker J. Biosynthesis of human colonic mucin: Muc2 is the prominent secretory mucin. Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, et al.

Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Hasnain SZ, Wang H, Ghia JE, Haq N, Deng Y, Velcich A, et al.

Mucin gene deficiency in mice impairs host resistance to an enteric parasitic infection. Bergstrom KS, Kissoon-Singh V, Gibson DL, Ma C, Montero M, Sham HP, et al.

Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog. Patel KK, Miyoshi H, Beatty WL, Head RD, Malvin NP, Cadwell K, et al. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production.

EMBO J. Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang JP, Brown EM, et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Gunawardene AR, Corfe BM, Staton CA. Classification and functions of enteroendocrine cells of the lower gastrointestinal tract.

Int J Exp Pathol. El-Salhy M, Gundersen D, Hatlebakk JG, Hausken T. Chromogranin a cell density as a diagnostic marker for lymphocytic colitis. Dig Dis Sci. Worthington JJ. The intestinal immunoendocrine axis: novel cross-talk between enteroendocrine cells and the immune system during infection and inflammatory disease.

Biochem Soc Trans. Hernandez-Trejo JA, Suarez-Perez D, Gutierrez-Martinez IZ, Fernandez-Vargas OE, Serrano C, Candelario-Martinez AA, et al.

Biochem J. Nagy P, Szatmari Z, Sandor GO, Lippai M, Hegedus K, Juhasz G. Ghia JE, Li N, Wang H, Collins M, Deng Y, El-Sharkawy RT, et al. Serotonin has a key role in pathogenesis of experimental colitis. Bischoff SC, Mailer R, Pabst O, Weier G, Sedlik W, Li Z, et al.

Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am J Physiol Gastrointest Liver Physiol. Soll C, Jang JH, Riener MO, Moritz W, Wild PJ, Graf R, et al.

Serotonin promotes tumor growth in human hepatocellular cancer. Imada T, Nakamura S, Hisamura R, Izuta Y, Jin K, Ito M, et al. Serotonin hormonally regulates lacrimal gland secretory function via the serotonin type 3a receptor. Sci Rep. Wu ZM, Zheng CH, Zhu ZH, Wu FT, Ni GL, Liang Y.

SiRNA-mediated serotonin transporter knockdown in the dorsal raphe nucleus rescues single prolonged stress-induced hippocampal autophagy in rats. J Neurol Sci. Lee J, Koehler J, Yusta B, Bahrami J, Matthews D, Rafii M, et al.

Enteroendocrine-derived glucagon-like peptide-2 controls intestinal amino acid transport. Mol Metab.

Kabat AM, Pott J, Maloy KJ. The mucosal immune system and its regulation by autophagy. Zhao Z, Fux B, Goodwin M, Dunay IR, Strong D, Miller BC, et al.

Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Li X, Ye Y, Zhou X, Huang C, Wu M.

Atg7 enhances host defense against infection via downregulation of superoxide but upregulation of nitric oxide. J Immunol. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, et al.

Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Marchiando AM, Ramanan D, Ding Y, Gomez LE, Hubbard-Lucey VM, Maurer K, et al. A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Martin PK, Marchiando A, Xu R, Rudensky E, Yeung F.

Schuster SL, et al. Nat Microbiol: Autophagy proteins suppress protective type I interferon signalling in response to the murine gut microbiota; Google Scholar. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.

Zhang H, Zheng L, McGovern DP, Hamill AM, Ichikawa R, Kanazawa Y, et al. Myeloid ATG16L1 facilitates host-Bacteria interactions in maintaining intestinal homeostasis. Zhang H, Zheng L, Chen J, Fukata M, Ichikawa R, Shih DQ, et al. Samie M, Lim J, Verschueren E, Baughman JM, Peng I, Wong A, et al.

Selective autophagy of the adaptor TRIF regulates innate inflammatory signaling. Nat Immunol. Strisciuglio C, Duijvestein M, Verhaar AP, Vos AC, van den Brink GR, Hommes DW, et al.

Impaired autophagy leads to abnormal dendritic cell-epithelial cell interactions. J Crohns Colitis. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A, et al.

In vivo requirement for Atg5 in antigen presentation by dendritic cells. Nimmerjahn F, Milosevic S, Behrends U, Jaffee EM, Pardoll DM, Bornkamm GW, et al. Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy.

Eur J Immunol. Pua HH, Guo J, Komatsu M, He YW. Autophagy is essential for mitochondrial clearance in mature T lymphocytes. Kovacs JR, Li C, Yang Q, Li G, Garcia IG, Ju S, et al.

Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery. Puleston DJ, Zhang H, Powell TJ, Lipina E, Sims S, Panse I, et al. Kabat AM, Harrison OJ, Riffelmacher T, Moghaddam AE, Pearson CF, Laing A, et al. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation.

Parekh VV, Wu L, Boyd KL, Williams JA, Gaddy JA, Olivares-Villagomez D, et al. Impaired autophagy, defective T cell homeostasis, and a wasting syndrome in mice with a T cell-specific deletion of Vps Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW.

A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med. Conway KL, Kuballa P, Khor B, Zhang M, Shi HN, Virgin HW, et al.

ATG5 regulates plasma cell differentiation. Chen M, Hong MJ, Sun H, Wang L, Shi X, Gilbert BE, et al. Essential role for autophagy in the maintenance of immunological memory against influenza infection.

Pengo N, Scolari M, Oliva L, Milan E, Mainoldi F, Raimondi A, et al. Plasma cells require autophagy for sustainable immunoglobulin production.

Chen M, Kodali S, Jang A, Kuai L, Wang J. Requirement for autophagy in the long-term persistence but not initial formation of memory B cells.

Xu X, Araki K, Li S, Han JH, Ye L, Tan WG, et al. Noureldein MH, Eid AA. Gut microbiota and mTOR signaling: insight on a new pathophysiological interaction. Microb Pathog. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease.

Campieri M, Gionchetti P. Bacteria as the cause of ulcerative colitis. Kwon YH, Denou E, Ghia JE, Rossi L, Fontes ME, Bernier SP, Shajib M, Banskota S, Collins SM, Surette MG, Khan WI.

Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis.

Cell Mol Gastroenterol Hepatol. Yang L, Liu C, Zhao W, He C, Ding J, Dai R, et al. Impaired autophagy in intestinal epithelial cells alters gut microbiota and host immune responses. Appl Environ Microbiol. Clark A, Mach N. Role of vitamin D in the hygiene hypothesis: the interplay between vitamin D, vitamin D receptors, gut microbiota, and immune response.

Wu S, Zhang YG, Lu R, Xia Y, Zhou D, Petrof EO, et al. Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis.

Yue C, Yang X, Li J, Chen X, Zhao X, Chen Y, et al. Trimethylamine N-oxide prime NLRP3 inflammasome via inhibiting ATG16L1-induced autophagy in colonic epithelial cells. Biochem Biophys Res Commun. Lin R, Jiang Y, Zhao XY, Guan Y, Qian W, Fu XC, et al. Four types of Bifidobacteria trigger autophagy response in intestinal epithelial cells.

J Dig Dis. Murthy A, Li Y, Peng I, Reichelt M, Katakam AK, Noubade R, et al. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3.

Massey DC, Parkes M. Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn's disease. Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V, et al. A synonymous variant in IRGM alters a binding site for miR and causes deregulation of IRGM-dependent xenophagy in Crohn's disease.

Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Plantinga TS, Crisan TO, Oosting M, van de Veerdonk FL, de Jong DJ, Philpott DJ, et al.

Crohn's disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2.

Liu TC, Naito T, Liu Z, VanDussen KL, Haritunians T, Li D, et al. LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn's disease patients.

JCI Insight. Rocha JD, Schlossmacher MG, Philpott DJ. LRRK2 and Nod2 promote lysozyme sorting in Paneth cells. Ravindran R, Loebbermann J, Nakaya HI, Khan N, Ma H, Gama L, et al. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Patel KK, Stappenbeck TS.

Autophagy and intestinal homeostasis. Annu Rev Physiol. Gardet A, Xavier RJ. Common alleles that influence autophagy and the risk for inflammatory bowel disease.

Curr Opin Immunol. Sibony M, Abdullah M, Greenfield L, Raju D, Wu T, Rodrigues DM, et al. Microbial disruption of autophagy alters expression of the RISC component AGO2, a critical regulator of the miRNA silencing pathway.

Tsuboi K, Nishitani M, Takakura A, Imai Y, Komatsu M, Kawashima H. Autophagy protects against colitis by the maintenance of Normal gut microflora and secretion of mucus. Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Bock J, Martinez-Naves E, et al.

Paneth cells as a site of origin for intestinal inflammation. Zhao J, Dong JN, Wang HG, Zhao M, Sun J, Zhu WM, et al.

Docosahexaenoic acid attenuated experimental chronic colitis in interleukin deficient mice by enhancing autophagy through inhibition of the mTOR pathway. JPEN J Parenter Enteral Nutr. Zhao J, Sun Y, Shi P, Dong JN, Zuo LG, Wang HG, et al. Celastrol ameliorates experimental colitis in IL deficient mice via the up-regulation of autophagy.

Int Immunopharmacol. Macias-Ceja DC, Cosin-Roger J, Ortiz-Masia D, Salvador P, Hernandez C, Esplugues JV, et al. Stimulation of autophagy prevents intestinal mucosal inflammation and ameliorates murine colitis.

Br J Pharmacol. Hu S, Chen M, Wang Y, Wang Z, Pei Y, Fan R, et al. Massey DC, Bredin F, Parkes M. Use of sirolimus rapamycin to treat refractory Crohn's disease. Grizotte-Lake M, Vaishnava S. Autophagy: suicide prevention hotline for the gut epithelium.

Burger E, Araujo A, Lopez-Yglesias A, Rajala MW, Geng L, Levine B, et al. Loss of Paneth cell autophagy causes acute susceptibility to toxoplasma gondii-mediated inflammation. Matsuzawa-Ishimoto Y, Shono Y, Gomez LE, Hubbard-Lucey VM, Cammer M, Neil J, et al.

Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium. Pott J, Kabat AM, Maloy KJ. Intestinal epithelial cell autophagy is required to protect against TNF-induced apoptosis during chronic colitis in mice.

Yuan Y, Ding D, Zhang N, Xia Z, Wang J, Yang H, et al. Cell Cycle. Download references. This work was supported by a grant from Canadian Institute of Health Research CIHR to Waliul I Khan reference number: Sabah Haq and Suhrid Banskota are recipients of Graduate Student Scholarship and Post-doctoral Fellowship Award from Farncombe Family Digestive Health Research Institute.

Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, L8N 3Z5, Canada. Department of Pathology and Molecular Medicine, McMaster University, Room 3N7, Hamilton, ON, L8N 3Z5, Canada.

You can also search for this author in PubMed Google Scholar. SH collected literature, designed and wrote the manuscript. JG edited and prepared manuscript for submission.

SB edited and WK edited, revised and designed the manuscript. All authors read and approved the final manuscript. Correspondence to Waliul I. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Besides, p62 overexpression via autophagy-lysosome promotes carcinogenesis via NF-κB flagging liberation, activating nuclear factor E2-related factor Nrf-2 , inducing ROS production, and leading to DNA damage. The contrast between these paradoxical features of autophagy makes the association with disease treatment more complex.

Notwithstanding, it has been recommended that in the initial phases of malignant growth, quality control via autophagy, especially over genome upkeep, suppresses carcinogenesis. Autophagy might organize the support or passage of cells into the G0 stage and subsequently forestall the unconstrained proliferation of tumor cells.

Conversely, autophagy might provide nutrition for cancer cells and assist their growth when suffering from metabolic pressure and oppose passing set off by chemotherapeutics [ 82 ]. Furthermore, autophagy promotes growth cell endurance in normal and cancer cells.

Although autophagy can postpone apoptosis, cell passing ultimately restricts autophagy. Apoptosis ordinarily escapes growing cells, granting supported endurance, movement, and protection from treatment.

The delayed pressure endurance managed by imperfect apoptosis occurs in cancer cells by either increased anti-apoptotic genes Bcl-2 and Bcl-xL or deficiency in pro-apoptotic genes Bax and Bak [ 83 ].

The shortfall of cell passing is insufficient to support the pressure endurance of growing cells. Thus, the pressure from glucose oxygen deprivation strongly enacts autophagy, upholding apoptotic cells' long-term endurance.

Cancer cells evading apoptosis can also obtain nutrition via autophagy when they endure pressure for a long time and enter a torpid condition. They can leave torpidity to continue cell multiplication when the pressure is released and typical development conditions are reestablished [ 84 ].

Hereditary or pharmacologic concealment of autophagy advances cell demise by putrefaction in vitro and in vivo, which suggests that growing and quiescent cells use autophagy to keep up with endurance in distressing conditions [ 85 ].

Autophagy limits these hypoxic districts, where it upholds growing cell endurance. Oxygen-detecting hypoxia-inducible factors activate autophagy alongside other metabolic factors and favor angiogenesis pathways unaffected by cell variation to metabolic pressure.

Autophagy induction in hypoxic areas might also hamper treatment due to proliferative cells that are resistant to treatment in these hypoxic areas. Hence, determining the cancer cell torpidity and recovery component and how to target this pathway to build novel anti-cancer strategies is essential.

Currently, lysosomotropism specialists e. On the other hand, autophagy can also effectively exhibit antitumor activity in some contexts, especially in focused growth cells or when blended with restorative mTOR hindrance.

In this case, autophagy might improve endurance, conceivably subverting treatment. Besides, various strategies using 3-MA, chloroquine, or hereditary manipulation of autophagy-related genes have shown that autophagy hindrance might sharpen growing cells to death, acting on assorted cytotoxic specialists [ 87 ].

Moreover, proteasome inhibitors can effectively trigger autophagy. Mechanistically, proteins can be degraded via two classical pathways: autophagy—lysosomal and ubiquitin—proteasome pathways. Inhibiting the ubiquitin—proteasome pathway activates the autophagy—lysosomal pathway.

For example, Bortezomib an FDA-approved proteasome inhibitor effectively enhances autophagy in colorectal cancer and myeloma cells [ 89 , 90 ]. Consistently, proteasome hindrance in prostate malignant growing cells by NPI can act through autophagy by an eIF2α-subordinate component that controls ATG function [ 91 ].

The concurrent inhibition of the two systems can result in a more effective strategy against cancer cells than the restraint of either pathway alone, which should be tested in the future.

In summary, this review provided a profound understanding of the relationship between inflammation and autophagy in various human disorders. Autophagy can assume fundamental roles in inflammatory diseases, infections, and carcinogenesis. A better comprehension of autophagy in different diseases has promising effects on developing improved treatments.

Meanwhile, autophagy studies are still being conducted, although their relevance to digestion, stress reaction, and cell demise pathways is recognized. Consequently, this cycle and their related reactions might provide data on how the host reacts to exogenous microorganisms and endogenous particles created under pressure conditions, yet these occasions can be re-molded by different stimuli and cell types.

Altogether, understanding how autophagy is regulated and directed, and the particularity related to cell utilization, requires further examination.

It will be essential to characterize and portray sub-atomic and biochemical features associated with the intricate exchange among autophagy and different pathologies to advance novel approaches for patients with neurodegenerative diseases and infections.

The field of autophagy in immunity and inflammation-related diseases continues to evolve in both fundamental and translational fields. In general, almost all human diseases possess an inflammatory component, which in turn provides a window of opportunity and a challenge to develop autophagy-based therapeutic strategies.

Considering the irreplaceable role of autophagy in the removal of the primary toxic entity causing disease and subsequently reducing the susceptibility to pro-death insults, which implying autophagy is a promising target mechanism from a therapeutic perspective.

Finally, various pre-clinical and clinical studies are needed to investigate the function of autophagy in several diseases. Münz C. Enhancing immunity through autophagy. Annu Rev Immunol. Article CAS PubMed Google Scholar. Virgin HW, Levine B. Autophagy genes in immunity. Nat Immunol.

Article CAS PubMed PubMed Central Google Scholar. Autophagy and autophagy-related proteins in cancer. Mol Cancer. Xiang H, Zhang J, Lin C, Zhang L, Liu B, Ouyang L.

Targeting autophagy-related protein kinases for potential therapeutic purpose. Acta Pharm Sin B. Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cybulsky AV. Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases.

Nat Rev Nephrol. Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. Chen GY, Nuñez G.

Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Li W, He P, Huang Y, Li YF, Lu J, Li M, et al.

Selective autophagy of intracellular organelles: recent research advances. Deretic V. Autophagy in inflammation, infection, and immunometabolism. Racanelli AC, Kikkers SA, Choi AMK, Cloonan SM. Autophagy and inflammation in chronic respiratory disease. Article PubMed PubMed Central Google Scholar.

Matsuzawa-Ishimoto Y, Hwang S, Cadwell K. Autophagy and Inflammation. Wen JH, Li DY, Liang S, Yang C, Tang JX, Liu HF. Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis. Front Immunol.

Liu T, Wang L, Liang P, Wang X, Liu Y, Cai J, et al. USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy. Cell Mol Immunol.

Sanjurjo L, Aran G, Téllez É, Amézaga N, Armengol C, López D, et al. CD5L promotes M2 macrophage polarization through autophagy-mediated upregulation of ID3. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol.

Kerr JS, Adriaanse BA, Greig NH, Mattson MP, Cader MZ, Bohr VA, et al. Trends Neurosci. Lou G, Palikaras K, Lautrup S, Scheibye-Knudsen M, Tavernarakis N, Fang EF. Mitophagy and neuroprotection. Trends Mol Med. Monkkonen T, Debnath J.

Inflammatory signaling cascades and autophagy in cancer. Gonzalez CD, Resnik R, Vaccaro MI. Secretory autophagy and its relevance in metabolic and degenerative disease. Front Endocrinol Lausanne. Article PubMed Google Scholar.

Bustos SO, Leal Santos N, Chammas R, Andrade LNS. Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma. Cancers Basel. Kraya AA, Piao S, Xu X, Zhang G, Herlyn M, Gimotty P, et al. Identification of secreted proteins that reflect autophagy dynamics within tumor cells.

Autophagy: an emerging immunological paradigm. J Immunol. Atg7 deficiency intensifies inflammasome activation and pyroptosis in pseudomonas sepsis. Li Q, Li L, Fei X, Zhang Y, Qi C, Hua S, et al.

Inhibition of autophagy with 3-methyladenine is protective in a lethal model of murine endotoxemia and polymicrobial sepsis. Innate Immun. Castillo EF, Dekonenko A, Arko-Mensah J, Mandell MA, Dupont N, Jiang S, et al.

Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc Natl Acad Sci USA. Autophagy in the pathogenesis of disease.

Arroyo DS, Gaviglio EA, Peralta Ramos JM, Bussi C, Rodriguez-Galan MC, Iribarren P. Autophagy in inflammation, infection, neurodegeneration and cancer. Int Immunopharmacol. Xiao Y, Cai W. Autophagy and bacterial infection. Adv Exp Med Biol. Onorati AV, Dyczynski M, Ojha R, Amaravadi RK.

Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol. Li W, Li Y, Siraj S, Jin H, Fan Y, Yang X, et al.

FUN14 domain-containing 1-mediated mitophagy suppresses hepatocarcinogenesis by inhibition of inflammasome activation in mice. Chen D, Xie J, Fiskesund R, Dong W, Liang X, Lv J, et al. Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype.

Nat Commun. DeVorkin L, Pavey N, Carleton G, Comber A, Ho C, Lim J, et al. Cell Rep. Swadling L, Pallett LJ, Diniz MO, Baker JM, Amin OE, Stegmann KA, et al. Poillet-Perez L, Sharp DW, Yang Y, Laddha SV, Ibrahim M, Bommareddy PK, et al. Autophagy promotes growth of tumors with high mutational burden by inhibiting a T cell immune response.

Nat Cancer. Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M, Gupta S, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Cunha LD, Yang M, Carter R, Guy C, Harris L, Crawford JC, et al.

LC3-associated phagocytosis in myeloid cells promotes tumor immune tolerance. Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Wang H, Hu S, Chen X, Shi H, Chen C, Sun L, et al. cGAS is essential for the antitumor effect of immune checkpoint blockade.

Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH, et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG.

Bravo-San Pedro JM, Kroemer G, Galluzzi L. Autophagy and mitophagy in cardiovascular disease. Circ Res. Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, et al. Autophagy in major human diseases. Embo j. Ren J, Zhang Y. Targeting autophagy in aging and aging-related cardiovascular diseases.

Trends Pharmacol Sci. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Ammanathan V, Vats S, Abraham IM, Manjithaya R. Xenophagy in cancer. Semin Cancer Biol. Wen X, Klionsky DJ.

How bacteria can block xenophagy: an insight from salmonella. Franco LH, Nair VR, Scharn CR, Xavier RJ, Torrealba JR, Shiloh MU, et al. The ubiquitin ligase smurf1 functions in selective autophagy of mycobacterium tuberculosis and anti-tuberculous host defense.

Cell Host Microbe. Jia J, Abudu YP, Claude-Taupin A, Gu Y, Kumar S, Choi SW, et al. Galectins control mTOR in response to endomembrane damage.

Mol Cell. Park S, Buck MD, Desai C, Zhang X, Loginicheva E, Martinez J, et al. Autophagy genes enhance murine gammaherpesvirus 68 reactivation from latency by preventing Virus-induced systemic inflammation.

Fung TS, Liu DX. Human coronavirus: host-pathogen interaction. Annu Rev Microbiol. Schneider WM, Luna JM, Hoffmann HH, Sánchez-Rivera FJ, Leal AA, Ashbrook AW, et al.

Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks. Berlin DA, Gulick RM, Martinez FJ. Severe covid N Engl J Med. Braun J, Loyal L, Frentsch M, Wendisch D, Georg P, Kurth F, et al. SARS-CoVreactive T cells in healthy donors and patients with COVID Mathew D, Giles JR, Baxter AE, Oldridge DA, Greenplate AR, Wu JE, et al.

Deep immune profiling of COVID patients reveals distinct immunotypes with therapeutic implications. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, et al. Jiang, M. Autophagy in proximal tubules protects against acute kidney injury. Jo, S.

Macrophages contribute to the initiation of ischaemic acute renal failure in rats. Jung, C. ULK-AtgFIP complexes mediate mTOR signaling to the autophagy machinery. Kim, M. Kim, Y. mTOR: a pharmacologic target for autophagy regulation. Kim, J. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk.

Kimura, T. Autophagy and kidney inflammatory. Autophagy 13, — Autophagy protects the proximal tubule from degeneration and acute ischemic injury.

Kinsey, G. Inflammation in acute kidney injury. Nephron Exp. Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. La Paquette, P. Cellular and molecular connections between autophagy and inflammation.

Lech, M. Macrophagy phenotype controls long-term AKI outcomes-kidney regeneration versus atrophy. Lee, S. Distinct macrophage phenotypes contribute to kidney injury and repair.

Leventhal, J. Autophagy limits endotoxemic acute kidney injury and alters renal tubular epithelia cell cytokine expression.

Levine, B. Biological functions of autophagy genes: a disease perspective. Cell , 11— Li, L. NKT cell activation mediates neutrophil INF-gamma production and renal ischemia-reperfusion injury.

Linfert, D. Lymphocytes and ischemia-reperfusion injury. Orlando 23, 1— Liu, M. A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity. Liu, S. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury.

Autophagy 8, — Liu, D. Youthful systemic milieu alleviates renal ischemia- reperfusion injury in elderly mice. Livingston, M. Autophagy in acute kidney injury. Lu, L. Increased macrophage infiltration and fractalkine expression in cisplatin-induced acute renal failure in mice.

Milica, B. Multiphoto imaging reveals axial differences in metabolic autofluorescence signals along the kidney proximal tubule. Mizushima, N. A brief history of autophagy from cell biology to physiology and disease. Autophagy: renovation of cells and tissues.

Cell , — The role of Atg proteins in autophagosome formation. Cell Dev. Monteiro, R. A role for regulatory T cells in renal acute kidney injury. Morgan, M. Crosstalk of reactive oxygen species and NF-kappaB signaling.

Cell Res. Nakahira, K. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome.

Netea-Maier, R. Modulation of inflammation by autophagy: consequences for human disease. Autophagy 12, — Periyasamy-Thandavan, S. Autophagy is cytopretective during cisplatin injury of renal proximal tubular cells. Qiu, S. Rabb, H. Inflammation in AKI: current understanding, key questions, and knowledge gaps.

Radi, Z. Immunopathogenesis of acute kidney injury. Renner, B. Saitoh, T. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature , — Sebastien, H.

AMPK: guardian of metabolism and mitochondrial homeostasis. Shi, C. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Singbartl, K. Kidney-immune system crosstalk in AKI.

Tadagavadi, R. Renal dendritic cells ameliorate nephrotoxic acute kidney injury. Takabatake, Y. Autophagy and the kidney: health and disease. Takahashi, A. Autophagy guards against cisplatin- induced acute kidney injury. Tan, X. Tanida, I. Autophagy basics. Wu, Y. The role of autophagy in kidney inflammatory injury via the NF-kB route induced by LPS.

Yang, S. Sulfatide-reactive natural killer T cells abrogate ischemia-reperfusion injury. Yokota, N. Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia-reperfusion injury. Zhang, L. MicroRNAb promotes lipopolysaccharide- induced inflammatory injury and alleviates autophagy through JNK and NF-κB pathways in HK-2 cells.

Zhang, C. Effect of ATM on inflammatory response and autophagy in renal tubular epithelial cells in LPS-induced septic AKI. Zhao, J. Ursolic acid exhibits anti-inflammatory effects through blocking TLR4-MyD88 pathway mediated by autophagy.

Cytokine 5, 1—7. Keywords: autophagy, inflammatory, acute kidney injury, immune cells, tubular epithelial cells. Citation: Gong L, Pan Q and Yang N Autophagy and Inflammation Regulation in Acute Kidney Injury. Received: 26 June ; Accepted: 25 August ; Published: 25 September Copyright © Gong, Pan and Yang.

This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY.

The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Top bar navigation. About us About us. Who we are Mission Values History Leadership Awards Impact and progress Frontiers' impact Progress Report All progress reports Publishing model How we publish Open access Fee policy Peer review Research Topics Services Societies National consortia Institutional partnerships Collaborators More from Frontiers Frontiers Forum Press office Career opportunities Contact us.

Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office.

REVIEW article Front. Renal Physiology and Pathophysiology. Autophagy and Inflammation Regulation in Acute Kidney Injury. A correction has been applied to this article in:. Introduction Acute kidney injury AKI , a common clinical syndrome, is often associated with the rapid loss of kidney function and high morbidity and mortality rates.

e PubMed Abstract CrossRef Full Text Google Scholar. x PubMed Abstract CrossRef Full Text Google Scholar.

Introduction Soleimanpour, S. Hydrogen Sulfide alleviates acute myocardial ischemia injury by modulating autophagy and inflammation response under oxidative stress. Cheung ZH, Ip NY. The gut microbiota shapes intestinal immune responses during health and disease. In addition, ATG9 and the VPS34 complex are also involved in regulating the formation of autophagosomes [ 24 ].
Autophagy and Inflammation Immunity 53, — Oxidative Isotonic drink consumption Cell Longev. When autophagy Muscle growth workout strategies inflammayion and their components, it also inhibits the function of pathogen PAMPs as inflammatory stimuli, thus inflqmmation the downstream inflammatory signaling pathway. Nonetheless, the inflammxtion dissection of Muscle growth workout strategies membrane dynamics, stimulated by the discovery of ATG autophagy-related genes in yeast 9has shed considerable light on this topic Table 1. Article CAS PubMed PubMed Central Google Scholar Harris J. Trafficking of the intracellular bacteria Yersinia pseudotuberculosis to acidic compartments was recently shown to be enhanced by genetic inhibition of autophagy Two classical AD hallmarks are the accumulation of p-tau protein and the deposition of Aβ plaques [ 73 ].
Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis

MicroRNAb miRb inhibits autophagy by activating the JNK and NF-κB signaling pathways and the expression of inflammatory cytokines TNF-a, IL-1β, and IL-6 and further reduces the viability HK-2 cells upon LPS stimulation, whereas miRb silencing exhibits reverse effects.

Moreover, the suppression of miRb expression alleviates LPS-induced kidney injury in LPS-induced AKI mice by reducing inflammation Zhang et al. Zhang et al. investigated the role of ataxia-telangiectasia mutated ATM in LPS-induced in vitro model of septic AKI and the relationship among ATM expression, tubular epithelial inflammatory response, and autophagy.

ATM knockdown in LPS-induced HK-2 cells significantly reduced the levels of LC3 and Beclin-1 and also inhibited the expression of inflammatory factors TNF-α, IL-1β, and IL The study suggested that LPS may induce autophagy in HK-2 cells through the ATM pathway, which could eventually lead to the upregulation of inflammatory factors Zhang et al.

Lipocalin-2 Lcn2 attenuates renal injury by lowering serum creatinine levels and reducing tubular epithelial cell death in mice. Fibroblast growth factor 10 FGF10 , a multifunctional member of the FGF family, has been reported to exert protective effects against kidney ischemic injury and preserve the histological integrity in a rat model.

Moreover, rapamycin can partially reverse the renoprotective effect of FGF10, which suggests that the mTOR pathway may be involved in this process Tan et al. Apoptosis-stimulating protein two of p53 ASPP2 is a proapoptotic component of the p53 binding protein family, which plays a key role in regulating apoptosis and cell growth.

Acute zinc chloride treatment in rats exerted a renoprotective effect in ischemic AKI, attenuated endoplasmic reticulum ER stress, and inhibited the expression of Beclin-1 and LAMP-2, which was correlated with inhibition of the expression of apoptosis-related factors caspase-9, caspase-3, and p-JNK and inflammation-related factors IL-1ß, IL-6, and MCP-1; Abdallah et al.

C-reactive protein CRP was recently reported to be closely associated with poor renal function in patients with AKI. CRP overexpression exacerbated the condition in AKI mice and increased the levels of serum creatinine and urea nitrogen.

Rapamycin, which is an autophagy inducer, rescues CRP-impaired autophagy and reduces injury in vivo. In addition, oxacalcitriol OCT , a synthetic vitamin D analog, inhibits the IRI-induced upregulation of TLR4 IFN-γ and sodium-hydrogen exchanger-1 NHE-1 and thereby exerts a renoprotective effect in ischemia AKI by inhibiting autophagy Hamzawy et al.

Hyperbaric oxygenation HBO treatment exerts a renoprotective effect in the IRI model of transplanted rat kidneys, which was observed to be mediated by the activation of cellular autophagy and the inhibition of inflammatory responses Bao et al.

Contrast-induced nephropathy CIN is a leading cause of hospital-acquired AKI. The CIN-induced AKI rat model exhibited renal dysfunction, increased mitophagy, mitochondrial fragmentation, ROS generation, and apoptosis in renal tubular cells, alongside increased autophagy and enhanced expression of inflammatory cytokines IL-6 and TNF-α in kidneys and serum.

The antioxidant 2,3,5,6-tetramethylpyrazine TMP can protect cells against CIN. In rats, TMP prevents CIN kidney injury in vivo by reversing the associated pathological processes.

In a cisplatin a chemotherapeutic drug -induced model of AKI, treatment of proximal tubule-specific autophagy-deficient mice with cisplatin led to severe mitochondrial damage and promoted ROS production, DNA damage, and p53 activation.

Autophagy protects kidney proximal tubules against AKI, possibly by alleviating DNA damage and destroying ROS-generating mitochondria Takahashi et al.

Thus far, studies on the role of autophagy in kidney proximal tubules have often yielded contradictory or unconvincing results Periyasamy-Thandavan et al. We speculate that the reasons for such conflicting data include 1 the use of different autophagy agonists and inhibitors, which are not entirely specific and may have some unknown targets Kimura et al.

The genetic tendencies in offspring of different strains of mice may account for the differences caused by gene deletion.

At present, autophagy in tubules and its inflammatory regulation remain poorly understood, and the detailed mechanism needs to be elucidated further Figure 3. Figure 3. Autophagy and inflammation regulation and outcomes in AKI. Both infectious and noninfectious processes can trigger an inflammatory response, following which parenchymal cells and immune cells can induce AKI, which, in turn, lead to influx of innate immune cells, mainly macrophages, neutrophils, and natural killer NK T cells.

Both cells of the innate immune system and adaptive immune effector cells are responsible for subsequent damage Th2 cells plasma B cells and repair Th1 and Treg cells, M2 macrophages.

Excessive inflammatory responses are a key aspect in AKI pathology. The vital roles played by autophagy in the regulation of kidney inflammation have only been recognized recently.

At present, we know that autophagy occurs actively in AKI kidney. Our review suggests that the potential of autophagy to restrict the detrimental effects of inflammation might add to its positive effects in inflammation alleviation Djavaheri-Mergny et al.

Novel therapeutic interventions designed to enhance autophagy might represent an attractive strategy to overcome insufficiencies in autophagy associated with inflammatory dysregulation during AKI Duann et al. Intervention strategies to induce autophagy in various AKI models include the use of autophagy activators, such as rapamycin or its analogs, and autophagy inhibitors, such as chloroquine or 3-MA, both of which have been explored as therapeutic agents in AKI Djavaheri-Mergny et al.

Additional specific autophagy inducers for potential therapeutic applications include autophagy-inducing peptide Shi et al. An improved understanding of the complex role of autophagy in inflammation regulation may facilitate the development of potential targets in future therapeutic interventions in AKI.

In addition, the data acquired in rodent models should be critically evaluated in clinically related investigations conducted in the future. The differences in kidney structure and sensitivity to toxic agents such as LPS and cisplatin between humans and mice may influence the susceptibility to AKI as well as the degree and nature of inflammation.

Moreover, rodents exhibit different results upon AKI injury based on their sex and strains, and we expect differences in the responses between humans and rodents owing to the expression of different immune cell markers and different lymphocyte expression ratios.

Autophagy functions may be different in different proximal tubule segments Milica et al. Compared to rodents, the kidney structure of a pig is more similar to that of a human. Therefore, studies conducted on a pig model are more conducive to transformation to clinical research, and the humanized mouse model may also partially compensate for such differences.

Future studies should focus on the identification of novel AKI animal models that effectively mimic the human inflammatory response, the recognition of novel inflammation mediators and targets for autophagy regulation, and critical assessment of the optimal time points and thresholds for autophagy intervention during AKI.

Overall, a precise understanding of the mechanism underlying the regulation of inflammatory response by autophagy will be beneficial in future therapeutic interventions. LG, QP, and NY designed the literature search and wrote the article with input from all authors. LG drafted the manuscript and designed the figures.

All authors discussed the results and commented on the manuscript. All authors contributed to the article and approved the submitted version. The work was supported by the Science and Technology Plan Project of the Guangdong Province grant number A and the Science and Technology Plan Project of Zhanjiang City grant numbers A and A The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abdallah, N. Zinc mitigates renal ischemia-reperfusion injury in rats by modulating oxidative stress, endoplasmic reticulum stress, and autophagy. doi: PubMed Abstract CrossRef Full Text Google Scholar. Andrade-Oliveira, V.

Gut bacteria products prevent AKI induced by ischemia-reperfusion. Ascon, D. Phenotypic and functional characterization of kidney-infiltrating lymphocytes in renal ischemia reperfusion injury. Bajwa, A. Dendritic cell sphingosine 1-phosphate receptor-3 regulates Th1-Th2 polarity in kidney ischemia-reperfusion injury.

Bao, D. Hyperbaric oxygenation protects against ischemia- reperfusion injury in transplanted rat kidneys by triggering autophagy and inhibiting inflammatory response. Bian, A. Downregulation of autophagy is associated with severe ischemia-reperfusion-induced acute kidney injury in overexpressing C-reactive protein mice.

PLoS One e Bolisetty, S. Neutrophils in acute kidney injury: not neutral any more. Kidney Int. Bonavia, A. A review of the role of immune cells in acute kidney injury.

Burne, M. Burne-Taney, M. B cell deficiency confers protection from renal ischemia reperfusion injury. Chen, G. Chen, Y. The regulation of autophagy-unanswered questions. Cell Sci. CrossRef Full Text Google Scholar.

Choi, M. Autophagy in kidney disease. Choi, A. Autophagy in inflammatory diseases. Cell Biol. Autophagy in human health and disease. Colleran, A. Autophagosomal IkappaB alpha degradation plays a role in the long term control of tumor necrosis factor-alpha induced nuclear factor-kappaB NF-kappaB activity.

De Paiva, V. Critical involvement of Th1 related cytokines in renal injuries induced by ischemia and reperfusion. Deretic, V.

Autophagy balances inflammation in innate immunity. Autophagy 14, — Autophagy in infection, inflammation and immunity.

Dikic, I. Mechanism and medical implications of mammalian autophagy. Djavaheri-Mergny, M. Regulation of autophagy by NFkB transcription factor and reactives oxygen species. Autophagy 3, — Dong, X. Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury.

Duann, P. Autophagy, innate immunity and tissue repair in acute kidney injury. Faubel, S. Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin IL -1β, IL, IL-6, and neutrophil infiltration in the kidney.

Galluzzi, L. Molecular definitions of autophagy and related processes. EMBO J. Glick, D. Autophagy: cellular and molecular mechanisms. Gong, X. Oxidative Med. Green, D. Mitochondria and the autophagy- inflammation - cell death axis in organismal aging.

Science , — Hampe, J. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1.

Hamzawy, M. He, Y. p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1. Hosokawa, N. Nutrient-dependent mTORC1 association with the ULK1-AtgFIP complex required for autophagy. Cell 20, — Hu, C.

The role of natural killer T cells in acute kidney injury: angel or evil? Choi, Y. Autophagy during Viral Infection - A Double-Edged Sword. Christgen, S. Toward Targeting Inflammasomes: Insights into Their Regulation and Activation.

Cell Res 30, — Cohen, J. Herpesvirus Latency. Conway, K. Atg16l1 Is Required for Autophagy in Intestinal Epithelial Cells and protection of Mice from Salmonella Infection. Gastroenterology , — Cullup, T.

Recessive Mutations in EPG5 Cause Vici Syndrome, a Multisystem Disorder with Defective Autophagy. Delgado, M. Toll-like Receptors Control Autophagy.

EMBO J. Deretic, V. Autophagy in Inflammation, Infection, and Immunometabolism. Immunity 54, — Autophagy Balances Inflammation in Innate Immunity. Autophagy 14, — Dinkins, C.

Roles of Autophagy in HIV Infection. Cel Biol. Dupont, N. Shigella Phagocytic Vacuolar Membrane Remnants Participate in the Cellular Response to Pathogen Invasion and Are Regulated by Autophagy.

Cell Host Microbe 6, — English, L. Autophagy Enhances the Presentation of Endogenous Viral Antigens on MHC Class I Duirng HSV-1 Infection.

Ferner, R. Chloroquine and Hydroxychloroquine in Covid BMJ , 9— Fields, J. HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders.

Galli, G. Immunometabolism of Macrophages in Bacterial Infections. Ge, Y. Autophagy and Proinflammatory Cytokines: Interactions and Clinical Implications.

Cytokine Growth Factor. Ghazy, R. A Systematic Review and Meta-Analysis on Chloroquine and Hydroxychloroquine as Monotherapy or Combined with Azithromycin in COVID Treatment.

Green, D. To Be or Not to Be? How Selective Autophagy and Cell Death Govern Cell Fate. Cell , 65— Gutierrez, M. Autophagy Is a Defense Mechanism Inhibiting BCG and Mycobacterium tuberculosis Survival in Infected Macrophages.

Cell , — Harris, J. Autophagy Controls IL-1β Secretion by Targeting Pro-IL-1β for Degradation. Hoffmann, M.

Chloroquine Does Not Inhibit Infection of Human Lung Cells with SARS-CoV Huang, J. Bacteria-autophagy Interplay: A Battle for Survival. Hunter, N. Cytokine Storms: Understanding COVID Immunity 53, 19— Iwasaki, A. A New Shield for a Cytokine Storm.

Jin, M. SnapShot: Selective Autophagy. Cell , 1—6. Judith, D. Species-specific Impact of the Autophagy Machinery on Chikungunya Virus Infection. EMBO Rep. Kazer, S. Evolution and Diversity of Immune Responses during Acute HIV Infection.

Immunity 53, — Kimmey, J. Unique Role for ATG5 in Neutrophil-Mediated Immunopathology during M. tuberculosis Infection. Kimura, T. TRIM-mediated Precision Autophagy Targets Cytoplasmic Regulators of Innate Immunity. Kroemer, B. Biological Functions of Autophagy Genes: A Disease Perspective.

Cell , 11— Lapierre, J. Critical Role of Beclin1 in HIV Tat and Morphine-Induced Inflammation and Calcium Release in Glial Cells from Autophagy Deficient Mouse. Neuroimmune Pharmacol.

Lawrence, T. The Nuclear Factor NF-kappaB Pathway in Inflammation. Cold Spring Harb. Ledur, P. Zika Virus Infection Leads to Mitochondrial Failure, Oxidative Stress and DNA Damage in Human iPSC-Derived Astrocytes.

Levine, B. Autophagy in the Pathogenesis of Disease. Cell , 27— Autophagy in Immunity and Inflammation. Li, F. Bba-molecular Basis Dis. Li, W. Selective Autophagy of Intracellular Organelles: Recent Research Advances. Theranostics 11, — Li, Z.

Shigella Evades Pyroptosis by Arginine ADP-Riboxanation of Caspase Liang, X. Protection against Fatal Sindbis Virus Encephalitis by Beclin, a Novel BclInteracting Protein. Liu, J. Hydroxychloroquine, a Less Toxic Derivative of Chloroquine, Is Effective in Inhibiting SARS-CoV-2 Infection In Vitro.

Cell Discov 6, 6—9. Liu, T. NF-κB Signaling in Inflammation. Liu, X. Autophagy Induced by DAMPs Facilitates the Inflammation Response in Lungs Undergoing Ischemia-Reperfusion Injury through Promoting TRAF6 Ubiquitination. Cell Death Differ 24, — Liu, Y.

Inflammation-Induced, STING-dependent Autophagy Restricts Zika Virus Infection in the Drosophila Brain. Cell Host Microbe 24, 57— Lu, Q. Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis.

Cell Host Microbe 19, — Lueschow, S. The Paneth Cell: The Curator and Defender of the Immature Small Intestine. Lupfer, C.

Receptor Interacting Protein Kinase 2-mediated Mitophagy Regulates Inflammasome Activation during Virus Infection.

Maisonnasse, P. Hydroxychloroquine Use against SARS-CoV-2 Infection in Non-human Primates. Mao, K. Xenophagy: A Battlefield between Host and Microbe, and a Possible Avenue for Cancer Treatment.

Autophagy 13, — Marino, J. Functional Impact of HIV-1 Tat on Cells of the CNS and its Role in HAND. Life Sci. Matsuzawa-Ishimoto, Y. Autophagy and Inflammation. Medzhitov, R. Transcriptional Control of the Inflammatory Response. Inflammation New Adventures of an Old Flame. Origin and Physiological Roles of Inflammation.

Mehto, S. Cel 73, — Miao, G. ORF3a of the COVID Virus SARS-CoV-2 Blocks HOPS Complex-Mediated Assembly of the SNARE Complex Required for Autolysosome Formation. Cel 56, — Mitchell, G. Innate Immunity to Intracellular Pathogens: Balancing Microbial Elimination and Inflammation.

Cell Host Microbe 22, — Mizushima, N. Autophagy: Renovation of Cells and Tissues. Moscat, J. p62 at the Crossroads of Autophagy, Apoptosis, and Cancer. Nakagawa, I. Autophagy Defends Cells against Invading Group A Streptococcus. Science Nakahira, K. Autophagy Proteins Regulate Innate Immune Response by Inhibiting NALP3 Inflammasome-Mediated Mitochondrial DNA Release.

Nathan, C. Nonresolving Inflamm. Cel , — CrossRef Full Text. Ogawa, M. Escape of Intracellular Shigella from Autophagy. Orvedahl, A. Eating the Enemy within: Autophagy in Infectious Diseases. Cel Death Differ 16, 57— Autophagy Protects against Sindbis Virus Infection of the Central Nervous System.

Cell Host Microbe 7, — Pan, Y. Interleukin-1 Beta Induces Autophagy of Mouse Preimplantation Embryos and Improves Blastocyst Quality.

Park, S. Autophagy Genes Enhance Murine Gammaherpesvirus 68 Reactivation from Latency by Preventing Virus-Induced Systemic Inflammation. Cell Host Microbe 19, 91— Pilli, M. TBK-1 Promotes Autophagy-Mediated Antimicrobial Defense by Controlling Autophagosome Maturation. Immunity 37, — Prieto, P.

Activation of Autophagy in Macrophages by Pro-resolving Lipid Mediators. Autophagy 11, — Qi, H. A Cytosolic Phospholipase A 2 -Initiated Lipid Mediator Pathway Induces Autophagy in Macrophages.

Ramanathan, K. Immunology of COVID Current State of the Science. The pathogenesis of heart failure following MI is intricately linked to the development of postinfarct ventricular remodeling. Structural, functional and geometric alterations in infarcted and noninfarcted myocardial segments lead to ventricular dilation, increased ventricular sphericity and cardiac dysfunction [ 29 ].

Myocardial remodeling and heart failure progression increase the frequency of arrhythmias and survival of MI patients with a poor prognosis [ 30 ]. The degree of postinfarct remodeling depends on the size of the infarct area and the quality of the cardiac repair.

Researchers have questioned the notion that inflammatory signaling prolongs ischemic injury [ 31 , 32 ]; however, inflammatory pathways undoubtedly play crucial roles in the dilatation and fibrotic remodeling of the infarcted heart, thereby driving the cardiac output of the injured myocardium, a key event in the pathogenesis of exhaustion.

The repair of damaged tissue depends on the regulation of inflammatory factor levels, and the process is accompanied by the activation of integrity-related mesenchymal stem cells in tissues [ 33 ]. In damaged tissue, hyperinflammation can further damage myocardial tissue or function [ 33 ].

Inflammation is a protective response during which the immune system activates and recruits a large number of inflammatory cells for infiltration when the body is injured or invaded by pathogens.

Autophagy can influence the systemic immune response and the inflammatory responses of specific cell types. Inflammation occurs mainly through pathogen-related molecular patterns or injury-related molecular patterns to induce multiprotein signal transduction cascades that secrete pro-inflammatory cytokines and activate adaptive immune responses.

Ligands of Toll-like and nucleotide oligomerization domain NOD receptors not only induce inflammatory responses but also induce autophagy.

In addition, studies have found that autophagy regulates Toll-like receptor TLR signals to enhance inflammatory infiltration [ 34 , 35 ]. Thus, autophagy is closely related to the occurrence of inflammatory diseases. This section mainly describes the relationship between autophagy and the inflammatory response in CVDs.

When the myocardium is infected or in a state of ischemia and hypoxia, immune cells participate in the occurrence and development of myocardial inflammation. Autophagy protects cells from excessive inflammation via two mechanisms. Cells can effectively remove strong stimulants of inflammation, such as damaged organelles or disease-causing microorganisms.

In addition, cells can protect other cells by inhibiting inflammatory complexes. Investigating the inflammatory response of immune cells from the perspective of autophagy with the goal of reducing the inflammatory response in CVDs is of great significance to improve patient prognoses.

Autophagy regulates the inflammatory microenvironment of myocardial injury. TNF-α , Tumor necrosis factor α, IL-1β , interleukin 1β, NETosis neutrophil extracellular traposis, ROS reactive oxygen species, NETs , neutrophil extracellular traps, CCL2 C-C motif chemokine ligand 2, TH1 helper T cell 1, Treg regulatory T cell, DC dendritic cell, IL interleukin 10, TGF-β transforming growth factor-β, IFN-γ interferon-γ.

Neutrophils phagocytose and inactivate microorganisms and remove pathogens through the fusion of phagocytic cells and particles and the formation of autophagic lysosomes.

The mechanism by which autophagy regulates neutrophil-mediated inflammatory injury is not clear at present. However, a large number of studies have shown that autophagy plays a key role in driving the inflammatory activity of neutrophils during myocardial injury [ 36 , 37 ].

Autophagy regulates ROS and cytokine production in neutrophils and is closely associated with myocardial injury.

One of the mechanisms by which neutrophils regulate cardiac injury involves the production of a large number of ROS in a reduced nicotinamide adenine dinucleotide phosphate-dependent manner through a respiratory burst, which directly leads to tissue damage through the modification of proteins and lipids [ 38 , 39 ].

Studies have found that neutrophils from bone marrow-specific mice lacking ATG7 or ATG5 show reduced ROS production mediated by nicotinamide adenine dinucleotide phosphate oxidase [ 40 ], suggesting that autophagy defects reduce neutrophil-mediated myocardial injury.

In addition, autophagy regulates neutrophil secretion of tumor necrosis factor TNF -α, interleukin IL -1β, IL-6 and other cytokines, aggravating the myocardial inflammatory microenvironment [ 41 ]. Autophagy inhibitors, such as 3-methyladenine, wortmannin, and bafilomycin A1, significantly reduced IL-1β secretion by neutrophils [ 42 ].

This finding suggests that autophagy may be associated with myocardial injury by regulating IL-1β secretion from neutrophils. Neutrophil extracellular trap cell death is a form of programmed cell death. Activated neutrophils release depolymerized chromatin extracellularly when stimulated by certain cytokines, pathogens or compounds.

The net structures are termed neutrophil extracellular traps NETs. NETs not only engulf and kill invasive pathogens but also act as self-antigens, which leads to a variety of acute and chronic inflammatory reactions. Studies have found an increase in NETs in the culprit arteries of patients with acute MI, and these structures may play a central role in artery-blocking thrombosis by promoting fibrin deposition and the formation of the fibrin network [ 43 ].

The data suggest that NETs may be related to the occurrence of MI. Moreover, NETs are positively correlated with infarct size, adverse cardiac events and left ventricular dysfunction in patients with MI [ 44—46 ]. It has been reported [ 47 ] that NETosis requires autophagy and superoxide production, and inhibition of autophagy leads to cell death characterized by apoptosis rather than NETosis.

Inhibition of mammalian target of rapamycin mTOR or autophagy activation by rapamycin can enhance the formation of NETs, whereas ATG5 deficiency can reduce the release of NETs [ 46 , 48 ], supporting the view that impaired neutrophil autophagy reduces NET release.

Another study [ 49 ] found that autophagy-induced increases in NET levels were detected in neutrophils isolated from patients with sepsis. Neutrophils isolated from patients with sepsis showed autophagy dysregulation, and enhanced autophagy improved survival by increasing NET levels in a mouse model of sepsis [ 50 ].

Together, these studies strongly support the idea that NETs are closely related to autophagy pathways in myocardial injury. As an important component of innate immunity, macrophages are widely present in the tissue structure, including the heart, and play an important role in the development of the myocardium, tissue repair and remodeling, and the immune response.

Autophagy in macrophages shows a wide range of functional characteristics that not only promote inflammation but also play a role in tissue repair [ 51 ]. Moreover, the characteristics of autophagy are different and complex during different stages of the same disease.

Therefore, in-depth analysis of the diversity of macrophage function regulated by autophagy is of great significance for identifying new targets for disease intervention. This section summarizes the role of autophagy in cardiac macrophages during myocardial injury.

Coronary artery occlusion leads to ischemic injury of cardiomyocytes. Macrophages not only cause an intense inflammatory response and ventricular remodeling but are also necessary for inflammatory regression and cardiac repair.

Myocardial injury induces the production and secretion of pro-inflammatory cytokines and chemokines by stationary macrophages, which trigger the metastasis of myeloid cells to the infarct site.

The inflammatory response induced by myocardial injury plays an important role in myocardial healing and scarring, whereas a continuous inflammatory response greatly promotes myocardial remodeling and leads to heart failure.

Apoptosis is a mechanism of debris removal and inflammation suppression during tissue injury and is closely related to macrophages. Metformin Met is a widely used hypoglycemic agent and has a significant cardioprotective effect during ischemic myocardial injury, such as acute MI AMI.

These results suggest that Met protects against ischemic myocardium injury by reducing the inflammatory response mediated by the macrophage autophagy—ROS—NLRP3 axis [ 52 ]. Reperfusion injury refers to the pathological process of the progressive aggravation of tissue injury when the ischemic myocardium is restored to normal perfusion after partial or complete acute obstruction of the coronary artery.

In macrophages, lysosomes are at the center of key cellular processes that activate inflammasomes [ 54 , 55 ]. Induced macrophage-specific overexpressed transcription factor EB TFEB is a major regulator of lysosomal biogenesis.

Javaheri et al. Moreover, this process did not require ATG5-dependent autophagy. This finding suggests that TFEB reprograms lysosomal lipid metabolism in macrophages to attenuate remodeling of myocardial injury, suggesting another mode in which lysosomal function influences inflammation.

T lymphocytes obtain inflammatory information through membrane receptors, antigen-specific receptors and soluble mediators, and each tissue subpopulation identifies the lesion site according to the information and adjusts the characteristics of lymphocytes themselves to adapt to the changes in the microenvironment [ 57 ].

T cells effectively respond to changes in the intracellular and extracellular environment through autophagy regulation.

Autophagy disorders may induce a variety of T-cell-related diseases [ 58 , 59 ]. In view of the potential application prospects of the T-cell autophagy pathway in the treatment of various diseases, this section summarizes the recent research progress that has been made in understanding the role of T-cell autophagy in regulating the inflammatory microenvironment that is present during myocardial injury.

The regulatory role of autophagy in T-cell function and the mechanism of autophagy abnormalities during the process of myocardial injury are also discussed.

Cecal ligation puncture CLP is the standard animal model for studying sepsis. The continuous spread of cecal contents into the abdominal cavity leads to the entry of bacteria into the bloodstream, ultimately leading to systemic inflammatory response syndrome and multiple organ dysfunction syndrome.

Sepsis cardiomyopathy is one of the most important organ injuries. Lin et al. These results suggest that autophagy may protect against T lymphocyte apoptosis and immunosuppression induced by sepsis. Tregs play a key role in inhibiting myocardial inflammation after MI and are considered a subset of lymphocytes with anti-inflammatory properties.

Deletion of ATG5 or ATG7 autophagy genes can regulate the immune homeostasis of Treg cells and reduce the number of Tregs [ 61 ]. The number of Tregs decreases with ischemic injury, and the adoptive transfer and expansion of Tregs can effectively reduce the development of ischemic tissue injury and promote repair [ 62 ].

Xia et al. In this model, Tregs were more highly enriched in the myocardium compared with the heart-draining lymph nodes. These results suggest that autophagy may participate in the regulation of myocardial injury by regulating Tregs.

Vascular endothelial cells constitute the continuous inner wall of the lumen of the cardiovascular system, which is a naturally formed blood vessel and a key node for maintaining homeostasis. Structural and functional injury of endothelial cells is the initial stage and an important marker of myocardial injury.

The process of injury includes cell swelling, microvascular embolism and eventual rupture of microvessels, leading to cell apoptosis or the extravasation of contents, which is an inflammatory response that results in the deterioration of the myocardial microenvironment. In most cases of myocardial injury, autophagy activation can enhance endothelial cell activity, protect cells and maintain the homeostasis of the tissue environment.

However, in some states, excessive autophagy destroys the protective barrier of endothelial cells, causes oxidative damage and ultimately promotes apoptosis [ 56 ].

Damaged microvessels cannot supply sufficient levels of oxygen, causing cardiomyocytes to swell and rupture and the subsequent worsening of the myocardial inflammatory microenvironment.

MI, myocarditis, diabetes and other conditions can lead to myocardial cell damage, and autophagy plays an important role in regulating the inflammatory microenvironment of damaged myocardial cells.

By regulating the autophagy-inflammation-related pathway of damaged cardiomyocytes, inflammatory cell infiltration and the levels of inflammatory factors can be reduced, alleviating cardiac injury [ 64—66 ]. NLRP3 is a typical inflammasome and plays an important role in the development of myocardial injury.

Autophagy of cardiomyocytes can reduce the inflammatory response by eliminating active inflammatory bodies and stimuli with indirect inflammatory effects, and the accumulation of cellular metabolites and damaged organelles is closely related to the pathogenesis of myocardial injury [ 67—69 ].

Studies have shown that serine protease inhibitors vaspin can reduce myocardial injury by enhancing autophagy and inhibiting NLRP3 inflammasome activation [ 70 ]. The inhibitory effect of vaspin on NLRP3 inflammasome activation may depend on the upregulation of autophagy and ROS inhibition.

The inhibition of SIRT1 can improve these adverse effects. Viral myocarditis is a virus-induced local or diffuse, acute and chronic inflammatory disease of the myocardium [ 73 ], of which Coxsackie virus B3 is one of the major causes [ 74 ].

Rapamycin can be used to treat parasitic infections [ 75 ]. No changes in circulation or cardiac parasitemia were noted, whereas the cardiac inflammatory response was downregulated. Among them, rapamycin-treated infected mice exhibited preserved cardiac electrical function and reduced levels of cardiac damage, myocarditis and tissue pro-inflammatory cytokines interferon-γ, TNF-α and IL These findings suggest that autophagy potentially played a role in maintaining cellular homeostasis and regulating inflammatory responses to ameliorate myocardial injury.

Aging is also an important factor in myocardial injury, and autophagy plays an important role in age-related cardiomyopathy. Cardiac senescent cardiomyopathy in mammals is characterized by myocardial hypertrophy and fibrosis, with a tendency toward myocardial cell apoptosis and autophagy [ 76 ].

The study investigated increased numbers of inflammatory cells in the hearts of older mice. A large number of autophagic vacuoles and lymphocyte clusters were present around the blood vessels that were not observed in the hearts of younger mice.

In addition, the hearts of aged mice showed higher levels of Beclin-1 and LC3II protein expression, which was consistent with the induction of the autophagy pathway.

However, other studies have found no difference in the expression of autophagy genes between the hearts of older and younger individuals, suggesting that the effects involve protein expression and occur after transcription. Vascular endothelial cells are an important part of the cardiovascular system and their integrity underlies the ability of the cardiovascular system to exert homeostatic regulatory mechanisms.

In addition, the secretion function of endothelial cells also plays an important role in the regulation of CVDs. Vascular endothelial dysfunction is the key and initial stage of myocardial injury, and the regulation of autophagy is closely related to a variety of vascular lesions caused by endothelial dysfunction.

Endothelial cells can secrete a variety of vasoactive substances, which can be divided into two categories according to their regulatory functions on vascular smooth muscle.

The first category comprises vasodilators, including nitric oxide NO , endothelial-derived hyperpolarizing factor and prostacyclin.

The other category includes vascular constrictors, such as endothelium-derived contracting factor, prostaglandin E2 and thromboxane A2. Decreased endothelial nitric oxide synthase eNOS function leads to vascular motor dysfunction in patients with congestive heart failure and many other pathologic syndromes, such as left ventricular remodeling and dysfunction.

Although the changes in cardiac function caused by NO are complex, numerous studies in recent years have demonstrated that the high expression of eNOS in both vascular endothelial cells and the myocardium can improve left ventricular function after MI [ 77 , 78 ].

eNOS participates in the protective role of ischemia postadaptation [ 79 ]. Inhibition of eNOS counteracts the improvement of autophagy by IPostC.

Urolithin A UA , a mitochondrial autophagy inducer, can reduce mitochondrial oxidative stress and stabilize mitochondrial membrane potential in endothelial cells to preserve mitochondrial function, upregulate cyclin D and E to maintain endothelial cell viability and improve endothelial cell proliferation.

UA inhibits mitochondrial fission, restores mitochondrial fusion and reduces the proportion of mitochondrial fragments in endothelial cells.

UA enhances mitochondrial biogenesis in endothelial cells by upregulating Sirtuin 3 and peroxisome proliferator-activated receptor γ coactivator 1-α [ 81 ]. In endothelial cells, autophagy can upregulate angiogenic activity and contribute to the repair of damaged endothelial cells by inducing prolonged hypoxia [ 82 ].

Mouse experiments also confirmed that autophagy activation can stimulate cell proliferation and regeneration near ischemic focal points. Inflammation occurs mainly through the innate immune system using pattern recognition receptors.

Toll-like and Nod-like receptors recognize exogenous or endogenous ligands and are activated, and a multiprotein signal transduction cascade is subsequently induced to promote the secretion of pro-inflammatory cytokines. Inflammatory responses are associated with myocardial ischemia, reperfusion injury, septic cardiomyopathy, diabetic cardiomyopathy and heart failure.

When myocardial injury occurs, organelles, microorganisms and a large number of damaged substances accumulate in cells Figure 1.

Autophagy regulates the inflammatory microenvironment and inhibits the inflammatory response through the clearance of cellular debris [ 83 ]. However, autophagy can promote the occurrence of the inflammatory response [ 84 ]. Therefore, autophagy has a bidirectional effect and methods for regulating the inflammatory microenvironment during myocardial injury have not been determined.

However, it is well known that autophagy and inflammation are closely associated with myocardial injury. Myocardial ischemia is the pathological state of coronary artery lumen occlusion or stenosis in coronary heart disease, which is characterized by limited blood supply to the heart.

During the state of myocardial ischemia, the lack of raw materials leads to a decrease in ATP synthesis, which induces autophagy to clear apoptotic cardiomyocytes, misfolded proteins and necrotic mitochondria and regulates the myocardial inflammatory microenvironment [ 85 ].

Protecting cardiomyocytes is a vital strategy for the treatment of acute MI. The infiltration of immune cells has been observed in border areas after acute MI, indicating suppression of the inflammatory reaction in ischemic cardiac regions [ 86 ].

It was found that inflammatory factors and autophagy signals were strongest during the first week and apoptotic signals peaked during the second week after ligation of the left coronary artery, and the increased level persisted until the fourth week [ 87 ].

The application of a TNF-α inhibitor significantly inhibited autophagy and promoted muscle cell apoptosis in the boundary region. These results suggest that the inflammatory response may play a protective role in early MI by stimulating autophagy in myocardial cells. Myocardial-associated transcription factor A MRTF-A exerts an inhibitory effect on MI.

Zhong et al. found that MRTF-A reduced the activity of the NLRP3 inflammasome and significantly increased the expression of autophagy proteins in ischemic myocardial tissue. Lipopolysaccharide and 3-methyladenine 3-MA abrogated the protective effect of MRTF-A.

Overexpression of MRTF-A and SIRT1 effectively reduced myocardial ischemia injury. This outcome was related to a decrease in inflammatory cytokine levels and an increase in autophagy-related protein levels. The inhibition of SIRT1 activity partially suppressed the cardiac protective effect induced by MRTF-A [ 88 ].

Superoxide dismutase 1 SOD1 -KO mice showed excessive oxidative stress after AMI, which was caused by increased apoptosis of ischemic cardiomyocytes and an inflammatory response.

In contrast, enhanced autophagy played a protective role. SOD1-KO mice had more severe myocardial inflammation after AMI than wild-type mice [ 89 ]. Vitamin D deficiency is associated with AMI [ 89 ].

A study found that vitamin D3 treatment enhanced the expression of LC3II and Beclin-1, reduced levels of inflammatory cell infiltration and the MI size in AMI mice, and decreased levels of inflammatory factors and MI markers, significantly alleviating AMI-induced myocardial cell apoptosis.

Moreover, Bcl-2 upregulates or downregulates cysteine aspartic acid specific protease 3 caspase-3 , caspase-9 and Bax expression. In addition, vitamin D3 enhanced the inhibition of PI3K, P-Akt and P-mTOR expression induced by AMI [ 65 ].

The above experiments suggest that the pathway can promote autophagy in AMI-injured myocardium, protect against myocardial injury, inhibit the inflammatory response and improve the myocardial microenvironment.

Autophagy is closely related to the regulation of the inflammatory response to reperfusion injury after myocardial ischemia. Reperfusion injury is mainly due to acute injury caused by oxidative stress, which leads to ROS production after cardiomyocytes restore blood perfusion, and autophagy can reduce oxidative stress [ 90 ].

At present, the effect of autophagy on myocardial injury remains unclear and further exploration is needed. Overall, the inflammatory environment promotes cell death during ischemia, whereas autophagy controls inflammation and protects myocardial function by inhibiting inflammasome activation.

However, prolonged excessive autophagy may lead to the opposite effect by damaging cardiomyocytes. Autophagy and the myocardial inflammatory environment jointly regulate the entire process of myocardial ischemia. Sepsis is a systemic inflammatory syndrome caused by infection that further develops into multiple organ dysfunction syndrome.

The heart is one of the most vulnerable target organs. Many patients with severe sepsis have a decreased LVEF [ 92 ].

Improving the myocardial inflammatory microenvironment may represent a bottleneck in the treatment of sepsis. In a mouse model of CLP sepsis, Hsieh et al. Electron microscopy confirmed that autophagic flow was blocked during the late stage of sepsis, which manifested as an increase in the formation of autophagosomes in the left ventricle.

However, reductions in their fusion with lysosomes hindered the degradation of autophagosomes, and the aggregation of autophagosomes promoted cardiac dysfunction and exacerbated septic cardiomyopathy.

Busch et al. Further studies showed that IL-1β activated NF-κB and its target genes, resulting in myocyte myosin protein atrophy and reduction, which was accompanied by increased autophagy gene expression.

Activation of the NLRP3 inflammasome induces cleavage of caspase-1 and IL-1β precursors into mature forms and their release, inducing downstream immune signaling responses.

Autophagy can clear NLRP3 inflammasome activators, such as intracellular blockers, reducing the inflammatory response [ 95 ]. When insufficiencies in autophagy result in failure to clear damaged mitochondria, they accumulate in the cell and cause oxidative stress.

Excessive ROS can activate downstream pathways to produce cascading inflammatory effects and worsen the inflammatory microenvironment. Mitochondria exist in a dynamic equilibrium state in which slightly damaged mitochondria can be repaired and complementarily fused with other damaged mitochondria into new mitochondria.

Mitochondria that cannot be repaired are degraded by lysosomes [ 96 ]. During the pathological process of SIC, excessive ROS lead to oxidative stress and mitochondrial DNA damage as well as impaired mitochondrial protein synthesis and respiratory function. If damaged mitochondria are cleared by autophagy, mitochondrial biosynthesis is activated, which can alleviate myocardial injury caused by inflammation [ 97 ].

The process of septic cardiomyopathy is always accompanied by inflammation. Local pathological sections often exhibit inflammatory cell infiltration and deterioration of the inflammatory microenvironment.

The mitochondrial structure and function of myocardial cells are damaged and mitochondrial autophagy is insufficient to clear damaged mitochondria.

These damaged mitochondria accumulate in the cell and cause oxidative stress, induce the production of a large number of ROS and promote the inflammatory cascade reaction [ 98 ]. A large number of cardiomyocytes with morphological characteristics similar to pyroptotic cells were observed in the SIC animal model, and the presence of these cells was closely related to the inflammatory microenvironment.

Autophagy can improve the inflammatory microenvironment by removing damaged DNA fragments, broken cell membranes, swollen organelles and cytoplasm.

Diabetic cardiomyopathy is one of the most important causes of death in patients with diabetes mellitus. Its pathological features mainly include structural and functional damage, including myocardial cell metabolism disorder, insulin resistance, oxidative stress, inflammatory response and neuroendocrine system disorders.

The pathogenesis of diabetic cardiomyopathy myocardial injury remains unclear, but among many factors, the inflammatory response may play the most important role in promoting diabetic cardiomyopathy progression [ 99 ]. Typical autophagy is inhibited in type 1 diabetic hearts, and the reduction in autophagy is an adaptive change in type 1 diabetes that has a certain protective effect on cardiomyocytes [ ].

Diabetes-induced heart injury was significantly weakened in Beclin 1- and ATGdeficient diabetic mouse models [ ]. These mice exhibited improved heart function and reduced levels of oxidative stress, interstitial fibrosis and myocardial cell apoptosis.

In contrast, diabetic cardiac damage dose-dependently exacerbated Beclin 1 overexpression. These results suggest that reduced autophagy may represent an adaptive response to limit cardiac dysfunction in type 1 diabetes, possibly through upregulation of selective autophagy.

Fenofibrate FF is a peroxisome proliferator-activated receptor α agonist that has reduced lipid levels in the clinic, and 3-MA or sirtinol has eliminated the preventive effect of FF on high-glucose production.

These results suggest that FF may prevent the myocardial inflammatory response and dysfunction induced by type 1 diabetes by increasing FGF21 levels, which may upregulate SIRT1-mediated autophagy.

In type 2 diabetes induced by a high-fat diet, increased activation of typical autophagy has a protective effect on the myocardium.

However, in type 2 diabetes induced by fructose and milk fat, increased activation of typical autophagy may aggravate myocardial injury [ ].

One study observed increased expression of the cardiac autophagy marker LC3B-II and its mediator Beclin-1 and decreased expression of P62 in patients with type 2 diabetes.

P62 was integrated into autophagosomes for effective degradation and promoted significant activation of apoptotic caspase These results suggest that increased autophagy activity occurs in type 2 diabetic hearts. Cardiovascular toxicity caused by chemotherapy drugs has been increasingly recognized as an important factor affecting the survival and prognosis of cancer patients.

The cardiotoxicity of anthracyclines is progressive and irreversible, with most symptoms appearing within 1 year of chemotherapy. The process of chemotherapy-related cardiomyopathy is always accompanied by inflammation, and both systemic and local inflammatory reactions occur.

The systemic inflammatory response mainly occurs during the end stage of heart failure, whereas the local inflammatory response is a key factor in the process of heart failure that undergoes various adaptive compensatory mechanisms until decompensation and ultimately changes in myocardial structure, function and phenotype occur [ ].

A recent study found that the IL-1 β concentration was positively associated with heart failure mortality. In addition, early heart failure was accompanied by elevated levels of inflammatory molecules and altered expression of genes involved in innate immunity, suggesting that inflammation and the innate immune system may represent an early response of cardiomyocytes to injury [ ].

Ma et al. In contrast, blocking TLR4 did not produce a similar phenomenon. Further studies showed that by disrupting the interaction between TLR2 and its endogenous ligand, the levels of inflammation and fibrosis in cardiomyocytes were reduced.

However, inhibition of TLR4 exacerbates cardiac dysfunction and myocardial fibrosis by amplifying inflammation and inhibiting autophagy. These results suggest that autophagy interacts with TLR2 and TLR4 and plays different roles in chemotherapy-related cardiomyopathy. In addition to attention focused on its established fundamental role in maintaining normal cellular phenotype and function, interest in how targeted modulation of autophagy can prevent myocardial injury has increased.

The use of autophagy as a therapeutic modality has gained widespread support in recent years.

Myocardial injury: where inflammation and autophagy meet | Burns & Trauma | Oxford Academic

Wei, J. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Kabat, A. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. eLife 5 , de Google Scholar. Dengjel, J.

Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Nedjic, J. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Ireland, J. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells.

Paludan, C. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Lee, Y. p62 plays a specific role in interferon-γ-induced presentation of a Toxoplasma vacuolar antigen.

Sakowski, E. Ubiquilin 1 promotes IFN-γ-induced xenophagy of Mycobacterium tuberculosis. Romao, S. Autophagy proteins stabilize pathogen-containing phagosomes for prolonged MHC II antigen processing. Microtubule-associated protein 1 light chain 3 alpha LC3 -associated phagocytosis is required for the efficient clearance of dead cells.

Brooks, C. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32 , — This study demonstrates that the autophagy pathway in DCs is crucial for antigen presentation during herpesvirus infection in vivo.

Gobeil, P. Herpes simplex virus gamma mBio 3 , e— Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. This study shows that autophagy induced by the nutrient sensor GCN2 promotes cross-presentation of viral antigens.

Jostins, L. Host—microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. This study identifies a role for the autophagy gene ATG16L1 in supporting intestinal Paneth cells. Patel, K. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production.

Adolph, T. Paneth cells as a site of origin for intestinal inflammation. Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection.

Gastroenterology , — Hubbard-Lucey, V. Autophagy gene atg16l1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41 , — Martin, L. Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma. PLoS ONE 7 , e Zhou, X.

Genetic association of PRDM1 - ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population. Diseases 70 , — CAS Google Scholar. Dickinson, J. IL13 activates autophagy to regulate secretion in airway epithelial cells. Clarke, A. Autophagy is activated in systemic lupus erythematosus and required for plasmablast development.

Diseases 74 , — Alessandri, C. T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy. FASEB J. Weindel, C. B cell autophagy mediates TLR7-dependent autoimmunity and inflammation. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells.

Huang, J. Activation of antibacterial autophagy by NADPH oxidases. De Luca, A. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans.

Schwerd, T. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease.

Luciani, A. Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Abdulrahman, B.

Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis. Autophagy 7 , — Renna, M. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection.

Pyo, J. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nature Commun. Starr, T. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle.

Cell Host Microbe 11 , 33—45 Kimmey, J. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. This study identifies a non-autophagy function of ATG5 in defence against M.

Reggiori, F. Coronaviruses hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Kageyama, S. The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella.

Cell 22 , — Sorbara, M. The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner.

Liu, E. Microbes Infect. Wellcome Trust Case Control Consortium. Genome-wide association study of 14, cases of seven common diseases and 3, shared controls.

Cullup, T. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Hakonarson, H. A genome-wide association study identifies KIAA as a type 1 diabetes gene. Soleimanpour, S. The diabetes susceptibility gene Clec16a regulates mitophagy.

Schuster, C. The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection.

Immunity 42 , — Smyth, D. PTPN22 Trp explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes.

Diabetes 57 , — Martinez, A. Chromosomal region 16p further evidence of increased predisposition to immune diseases. Diseases 69 , — Scharl, M. Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy.

Bowel Dis. Yang, Z. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. Download references. The author would like to thank V. Torres New York University School of Medicine and members of the Cadwell laboratory for comments on the manuscript.

is supported by NIH grants DK, DK, HL, Stony Wold-Herbert Fund, and philanthropic support from Bernard Levine. is a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases.

and the Department of Microbiology, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, , New York, USA.

You can also search for this author in PubMed Google Scholar. Correspondence to Ken Cadwell. An evolutionarily conserved process in which double-membrane vesicles sequester intracellular contents such as damaged organelles and macromolecules and target them for degradation through fusion with lysosomes.

A cell-intrinsic defence mechanism involving the selective degradation of microorganisms such as bacteria, fungi, parasites and viruses through an autophagy-related mechanism.

A prototypical adaptor protein that targets ubiquitylated proteins for selective autophagy by binding ubiquitin and LC3. Through incorporation into the autophagosome, SQSTM1 itself becomes a substrate for autophagic degradation. A multi-protein oligomer that catalyses the autoactivation of caspase 1, which cleaves pro-IL-1β and pro-IL to produce the active forms of these cytokines.

An inflammatory form of programmed cell death that is dependent on inflammasome-mediated activation of caspase 1. Vesicles derived from the bacterial outer membrane that can be immunogenic and mediate interactions between commensal or pathogenic bacteria and the host.

B1 B cells are a group of self-renewing, autoreactive B cells with a limited B cell receptor repertoire. These cells are mainly found in the peritoneal cavity and the pleural cavity.

A self-peptide that incorporates the amino acid citrulline. These peptides are generated post-translationally by peptidylarginine deiminases. The citrulline moiety is the essential part of the antigenic determinant towards which characteristic autoantibodies in patients with rheumatoid arthritis are generated.

This exogenous antigen must be taken up by APCs and then re-routed to the MHC class I pathway of antigen presentation. Together with ulcerative colitis, Crohn disease is one of the two main forms of chronic inflammatory bowel disease IBD. It most commonly affects the lower portion of the small intestine, resulting in symptoms of abdominal pain, diarrhoea, fever and weight loss.

Analysis of the strong genetic predisposition led to the identification of mutations in the NOD2 gene that are particularly strongly associated with ileal disease, but not with ulcerative colitis. Endoplasmic reticulum stress pathway.

A conserved stress response pathway that senses the accumulation of unfolded proteins in the endoplasmic reticulum. A procedure in which HSCs from bone marrow or blood are transplanted to treat leukaemia and other disorders. A common complication of HSCT in which allogeneic T cells derived from a non-identical donor attack healthy tissue in the recipient.

An inherited disorder caused by defective oxidase activity in the respiratory burst of phagocytes. It results from mutations in any of four genes that are necessary to generate the superoxide radicals required for neutrophil antimicrobial function.

Affected patients suffer from increased susceptibility to recurrent infections. Reprints and permissions. Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 16 , — Download citation.

Published : 03 October Issue Date : November Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. nature nature reviews immunology review articles article. Download PDF. Subjects Adaptive immunity Autophagy Innate immunity.

Key Points The cellular degradative process of autophagy participates in multiple aspects of immunity, including cell-autonomous defence, innate immune signalling and antigen presentation.

Abstract Autophagy has broad functions in immunity, ranging from cell-autonomous defence to coordination of complex multicellular immune responses. Inflammasomes and adaptive immune responses Article 18 February The STING1 network regulates autophagy and cell death Article Open access 02 June Autophagy and microbial pathogenesis Article 02 January Main Macroautophagy, more commonly referred to simply as autophagy , is a fundamental cellular process in eukaryotes that is essential for responding and adapting to changes in the environment.

Box 1: Autophagosome biogenesis and autophagy-related proteins The generation of the autophagosome is mediated by the sequential activities of three key protein complexes: the ULK1 complex comprising ULK1, FIP, ATG13 and ATG , the phosphoinositide 3-kinase catalytic subunit type III PI3KC3 complex comprising beclin 1, vacuolar protein sorting 34 VPS34 , VPS15 and ATG14L , and the ATG16L1 complex comprising ATG16L1, ATG5 and ATG The role of autophagy in immunity Autophagy can eliminate an infectious threat by promoting a form of autophagy termed xenophagy , whereby intracellular pathogens such as viruses, bacteria and protozoa are trapped within an autophagosome and targeted to the lysosome for destruction.

Box 2: Non-canonical autophagy and immunity Several processes have been described in which subsets of the canonical autophagy pathway see box figure, part a contribute to immune responses, frequently independent of autophagosome formation.

Convergence of autophagy and immune signalling Amino acid starvation during bacterial infection can induce autophagy 27 , raising the possibility that sensing changes in nutrient availability is an ancient mechanism to initiate autophagy in response to infectious threats.

Figure 1: Crosstalk between Toll-like receptor and NOD-like receptor signalling and autophagy. Full size image. Figure 2: Intersection between autophagy and cytokines. Figure 3: Autophagy coordinates a multicellular adaptive immune response. Autophagy in immunity and disease Autophagy and adaptive immunity.

Table 1 Examples of autophagy genetic variants associated with chronic inflammatory disorders Full size table. Conclusion Autophagy and related processes regulate intracellular trafficking of pathogens, the production of inflammatory mediators and the viability of cells that coordinate immunity.

Similar content being viewed by others. References Russell, R. CAS PubMed PubMed Central Google Scholar Ge, L. PubMed PubMed Central Google Scholar Hamasaki, M. CAS PubMed Google Scholar Dooley, H.

CAS PubMed PubMed Central Google Scholar Randow, F. CAS PubMed PubMed Central Google Scholar Choy, A. CAS PubMed PubMed Central Google Scholar Chen, Y. CAS PubMed PubMed Central Google Scholar Martinez, J.

CAS PubMed PubMed Central Google Scholar Zhao, Z. CAS PubMed PubMed Central Google Scholar Hwang, S. CAS PubMed PubMed Central Google Scholar Choi, J. CAS PubMed PubMed Central Google Scholar Selleck, E. CAS PubMed PubMed Central Google Scholar Ohshima, J. CAS PubMed Google Scholar Haldar, A.

PubMed PubMed Central Google Scholar Park, S. CAS PubMed PubMed Central Google Scholar Shoji-Kawata, S. CAS PubMed PubMed Central Google Scholar Orvedahl, A. CAS PubMed PubMed Central Google Scholar Kernbauer, E. CAS PubMed PubMed Central Google Scholar Cadwell, K.

CAS PubMed PubMed Central Google Scholar Visvikis, O. CAS PubMed PubMed Central Google Scholar Maurer, K. CAS PubMed PubMed Central Google Scholar Figueiredo, N. CAS PubMed PubMed Central Google Scholar Medzhitov, R. CAS PubMed PubMed Central Google Scholar Marchiando, A. CAS PubMed Google Scholar Park, S.

CAS PubMed PubMed Central Google Scholar Lu, Q. CAS PubMed PubMed Central Google Scholar Tattoli, I. CAS PubMed Google Scholar Saitoh, T. CAS PubMed Google Scholar Nakahira, K. CAS PubMed Google Scholar Zhong, Z. CAS PubMed PubMed Central Google Scholar Dupont, N.

CAS PubMed Google Scholar Meunier, E. CAS PubMed Google Scholar Kreibich, S. CAS PubMed Google Scholar Suzuki, T. PubMed PubMed Central Google Scholar Byrne, B. CAS PubMed PubMed Central Google Scholar Shi, C.

CAS PubMed PubMed Central Google Scholar Bodemann, B. CAS PubMed PubMed Central Google Scholar Ravindran, R. CAS PubMed PubMed Central Google Scholar Wlodarska, M.

CAS PubMed PubMed Central Google Scholar Travassos, L. CAS PubMed Google Scholar Cooney, R. CAS PubMed Google Scholar Homer, C. CAS PubMed PubMed Central Google Scholar Anand, P. CAS PubMed PubMed Central Google Scholar Irving, A.

CAS PubMed Google Scholar Chauhan, S. CAS PubMed PubMed Central Google Scholar Plantinga, T. CAS PubMed Google Scholar Buffen, K. CAS PubMed PubMed Central Google Scholar Lassen, K.

CAS PubMed PubMed Central Google Scholar Murthy, A. CAS PubMed Google Scholar Lupfer, C. CAS PubMed PubMed Central Google Scholar Wen, Z.

CAS PubMed Google Scholar Chu, H. CAS PubMed PubMed Central Google Scholar Xu, Y. CAS PubMed PubMed Central Google Scholar Delgado, M.

PubMed PubMed Central Google Scholar Meijer, A. CAS PubMed Google Scholar Fujita, K. CAS PubMed PubMed Central Google Scholar Wild, P. CAS PubMed PubMed Central Google Scholar Moy, R. CAS PubMed Google Scholar Benjamin, J. CAS PubMed PubMed Central Google Scholar Lee, H. CAS PubMed Google Scholar Henault, J.

CAS PubMed PubMed Central Google Scholar Sanjuan, M. CAS PubMed Google Scholar Akoumianaki, T. CAS PubMed Google Scholar Katsuragi, Y. CAS PubMed Google Scholar Lee, H. CAS PubMed Google Scholar Kim, J. CAS PubMed Google Scholar Lei, Y. CAS PubMed PubMed Central Google Scholar Xia, M.

PubMed PubMed Central Google Scholar Zhao, Y. CAS PubMed PubMed Central Google Scholar Tal, M. CAS PubMed PubMed Central Google Scholar Jounai, N.

CAS PubMed PubMed Central Google Scholar Saitoh, T. CAS PubMed PubMed Central Google Scholar Konno, H. CAS PubMed Google Scholar Liang, Q. CAS PubMed PubMed Central Google Scholar Lan, Y. CAS PubMed PubMed Central Google Scholar Mathew, R. CAS PubMed PubMed Central Google Scholar Grimm, W. CAS PubMed Google Scholar Gutierrez, M.

CAS PubMed Google Scholar Harris, J. CAS PubMed Google Scholar Mostowy, S. CAS PubMed PubMed Central Google Scholar Matsuzawa, T. CAS PubMed Google Scholar Chang, Y. CAS PubMed PubMed Central Google Scholar Boonhok, R. CAS PubMed PubMed Central Google Scholar Shen, S. CAS PubMed Google Scholar Van Grol, J.

PubMed PubMed Central Google Scholar Terawaki, S. CAS PubMed PubMed Central Google Scholar Cullen, S. CAS PubMed Google Scholar Zhang, M. PubMed PubMed Central Google Scholar Pilli, M.

CAS PubMed PubMed Central Google Scholar Castillo, E. CAS PubMed PubMed Central Google Scholar Lee, J. CAS PubMed PubMed Central Google Scholar Peral de Castro, C.

CAS PubMed Google Scholar Ding, Y. CAS PubMed PubMed Central Google Scholar Trinchieri, G. CAS PubMed PubMed Central Google Scholar Mello Pde, A. PubMed Google Scholar Biswas, D. PubMed PubMed Central Google Scholar Takenouchi, T.

CAS PubMed Google Scholar Bian, S. CAS PubMed PubMed Central Google Scholar Martins, I. CAS PubMed Google Scholar Michaud, M. CAS PubMed Google Scholar Tang, D.

CAS PubMed PubMed Central Google Scholar Kang, R. CAS PubMed PubMed Central Google Scholar Zhu, X. PubMed PubMed Central Google Scholar Yanai, H. CAS PubMed PubMed Central Google Scholar Pua, H. CAS PubMed PubMed Central Google Scholar Stephenson, L.

CAS PubMed PubMed Central Google Scholar Jia, W. CAS PubMed Google Scholar Kovacs, J. CAS PubMed Google Scholar Pei, B. CAS PubMed Google Scholar Willinger, T. CAS PubMed PubMed Central Google Scholar Matsuzawa, Y. CAS PubMed PubMed Central Google Scholar Xu, X. CAS PubMed PubMed Central Google Scholar O'Sullivan, T.

CAS PubMed PubMed Central Google Scholar Puleston, D. PubMed Central Google Scholar Schlie, K. CAS PubMed Google Scholar Henson, S. CAS PubMed PubMed Central Google Scholar Hubbard, V.

CAS PubMed Google Scholar Miller, B. CAS PubMed Google Scholar Conway, K. CAS PubMed PubMed Central Google Scholar Pengo, N. CAS PubMed Google Scholar Paul, S. CAS PubMed PubMed Central Google Scholar Wei, J. CAS PubMed PubMed Central Google Scholar Kabat, A.

Google Scholar Dengjel, J. CAS PubMed PubMed Central Google Scholar Nedjic, J. CAS PubMed Google Scholar Ireland, J. CAS PubMed PubMed Central Google Scholar Paludan, C. CAS PubMed Google Scholar Lee, Y. CAS PubMed Google Scholar Sakowski, E. PubMed PubMed Central Google Scholar Romao, S.

CAS PubMed PubMed Central Google Scholar Brooks, C. CAS PubMed PubMed Central Google Scholar Gobeil, P. CAS PubMed Google Scholar Jostins, L. CAS PubMed PubMed Central Google Scholar Patel, K.

CAS PubMed PubMed Central Google Scholar Adolph, T. CAS PubMed PubMed Central Google Scholar Conway, K.

CAS PubMed Google Scholar Hubbard-Lucey, V. CAS PubMed PubMed Central Google Scholar Martin, L. CAS PubMed PubMed Central Google Scholar Zhou, X. CAS Google Scholar Dickinson, J.

PubMed PubMed Central Google Scholar Clarke, A. Google Scholar Alessandri, C. CAS PubMed PubMed Central Google Scholar Weindel, C. CAS PubMed PubMed Central Google Scholar Huang, J.

CAS PubMed PubMed Central Google Scholar De Luca, A. CAS PubMed Google Scholar De Luca, A. CAS PubMed PubMed Central Google Scholar Schwerd, T. CAS PubMed Google Scholar Abdulrahman, B. CAS PubMed PubMed Central Google Scholar Renna, M. CAS PubMed PubMed Central Google Scholar Pyo, J.

Google Scholar Starr, T. CAS PubMed PubMed Central Google Scholar Kimmey, J. CAS PubMed PubMed Central Google Scholar Reggiori, F. CAS PubMed PubMed Central Google Scholar Kageyama, S.

CAS PubMed PubMed Central Google Scholar Sorbara, M. For example, myeloid-specific Fip, Atg5, and Atg7 upregulation raises basal respiratory inflammation and protects against influenzas or reactivation herpesvirus [ 53 ].

Recently, some studies demonstrated that autophagy is associated with SARS-CoV-2 infections since the coronavirus and autophagosome are double membrane structures with slight differences [ 54 ].

Additionally, CRISPR genomic screens in cells deficient in type I IFN-inducing frameworks have demonstrated that critical autophagy genes TMEM41B and VMP1 participate in the cytopathic effect CPE of SARS-CoV-2, while several autophagy-related genes ATG3, ATG5, ATG7, and ATG12 might suppress CPE [ 55 , 56 ].

However, the reason for the high morbidity and mortality of coronavirus disease COVID is still elusive. Changes from asymptomatic infections to respiratory failure involve various organs and tissues [ 57 ].

Interestingly, the spike protein of severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 crosslinks with T cells or three distinct immunotypes [ 58 ].

Studies have also revealed contradictory findings during different infections: hereditary deficiency in Toll-like receptor 3 TLR3 —and TANK-binding kinase 1 TBK1 -mediated type I IFN signaling [] are associated with resistant type I IFN signaling in severe COVID infection patients [ 59 ].

Notably, TLR3 and double-stranded RNA dsRNA ligands do not induce autophagy, but TBK1 is relevant to autophagy [ 60 , 61 ]. Hence, autophagy and type I IFN frameworks are connected. Interchanges among autophagy and type I IFN and how autophagy influences different signaling can promote or alleviate inflammation reactions when exposed to SARS-CoV Therefore, the internal connections between autophagy and SARS-CoV-2 should be explored in greater depth.

The pathological mechanism for CD remains unclear, but some studies have uncovered three main pathways involved in CD: ATG16L1, insusceptibility-related GTPase family M IRGM , and nucleotide oligomerization domain contain protein 2 NOD2 [ 63 ].

We previously mentioned that ATG16L1 is fundamental for the legitimate extension of the separation layer. IRGM induces autophagy through IFN-γ, which prompted by bacterial infections [ 64 ].

In parallel, NOD2, an intracellular PRR of the NLR family, is responsible for communication in a predetermined number of tissues and cells that incorporates Paneth and monocyte-inferred cells. NOD2 initiates ATG16L1 to bacterial passage destinations, focusing on microscopic organisms for autophagic corruption [ 65 ].

Surprisingly, recent studies have demonstrated that NOD2 acts by recognizing bacterial ligand muramyl dipeptide MDP , inducing autophagy in essential antigen-presenting cells and monocyte-derived dendritic cells DCs. This peculiarity demands NOD2 and the NOD2 flagging arbiter RIPK-2, but not NALP3, a PRR that also perceives MDP.

Different groups have found that NOD2-instigated autophagy requires autophagy proteins, including PI3K, ATG5, ATG7, and ATG16L. Some studies have proposed that ATG16L1 TA variations decrease the autophagic freedom of intestinal microorganisms, such as disciple intrusive Escherichia coli or Salmonella typhimurium.

A previous review also depicted that ATG16L1 changes in mice lead to irregularities pertinent to CD development and progression [ 67 ].

The authors found a strong hereditary association between the ATG16L1 mutation and a particular strain of intestinal norovirus infection. Besides vulnerability quality cooperation, this infection modifies the transcriptional mark of Paneth cells and exacerbates immune reactions in mice treated with the harmful substance dextran sodium sulfate by increasing TNFα and IFNγ production and commensal microbes.

Furthermore, macrophages from mice lacking ATG16L1 in hematopoietic cells produce more IL-1β after LPS injection or infection with painless intestinal microorganisms. These mice are profoundly delicate to sodium sulfate-instigated colitis, suggesting that enhanced production of pro-inflammatory cytokines by macrophages might promote gastrointestinal harm in ATG16L1-subordinate CD.

Generally, decreased autophagy might change xenophagic bacterial flexibility, promoting cytokine production and extracellular discharge pathways and advancing CD pathogenesis [ 68 ].

Its etiology is portrayed by the occurrence of intracellular incorporations namely Lewy bodies , which contains α-synuclein and ubiquitin proteins, autophagosomes, and harmed mitochondria. The most common PD type is irregular PD, albeit family heredity is relevant [ 69 ]. Moreover, many studies have demonstrated that various pro-inflammatory cytokines participate in PD pathogenesis, such as TNF-α, IL-4, IL-6, IL, and IL-1β [ 70 ].

Several factors, such as a-synuclein, can serve as DAMPs to recognize PRRs, and leucine-rich repeat kinase 2 LRRK2 from the RIPK family and are involved in autophagy induction. Exogenous overexpression of a-synuclein leads to lysosomal damage and autophagy, which can be stimulated by tau protein related to Alzheimer's disease [ 71 ].

Exceptionally compelling is the framework comprising E3 ubiquitin ligase PRKN and PINK1 fit for driving mitophagy. However, in animal models, PINK1 and PRKN are not associated with PD. Additionally, transformations might enhance α-synuclein levels and induce familial PD.

Although autophagy is reversed by A53T overexpression, the overabundance of intracellular α-synuclein disables autophagy by restraining the small GTPase Rab-1A.

Finally, increased α-synuclein expression can induce protein accumulation and diminish autophagy, decreasing mitophagy and increasing neuronal apoptosis.

Two classical AD hallmarks are the accumulation of p-tau protein and the deposition of Aβ plaques [ 73 ]. These perceptions proposed that imperfections in autophagic development might be an overall element of AD pathology.

For example, in AD, autophagy might be weakened by autophagosome corruption and autophagosome formation, albeit those effects might fluctuate according to genotype and diseased phase. Hereditary examinations have also demonstrated a few transformations that induce intriguing familial AD types, such as the mutation of amyloid antecedent protein APP , presenilin-1, and presenilin-1—1 PS 1 and 2 [ 75 , 76 ].

Also, autophagy might be downregulated during autophagosome development in AD patients. Compared to healthy individuals, AD patients show diminished Beclin-1 articulation, which might prompt disability in autophagic movement. Beclin-1 heterozygous knockout in mice that express the AD-related human APP leads to APP and Aβ accumulation and displays more extreme neurodegeneration contrasted with Beclin-1 WT mice.

Additionally, pathogenic APP and tau are corrupted via autophagy. Consistently, 3-MA, a specific autophagy inhibitor, increments tau harmfulness, while rapamycin autophagy inducer diminishes tau effects in the cell [ 77 ]. Nonetheless, a previous review has shown that 3-MA or Beclin-1 knockdown could reduce Aβ disposition in neuroblastoma and glioma cells [ 78 ].

The discussion on the cytoprotective versus cytotoxic roles of autophagy in AD models might be clarified by assessing the autophagic motion and the level of lysosomal imperfection for each situation. Further examinations are expected to expand the role of autophagy in AD.

Autophagy was first identified as a key mechanism in cancer development. A cancer-suppressive role for autophagy corroborates this.

Interestingly, this idea has been challenged by some that propose that autophagy can support oncogenesis because it can assist growth cell endurance [ 79 ].

A growth silencer engaged with the upstream restraint of mammalian target of rapamycin mTOR flagging PTEN, TSC1, and TSC2 turns autophagy on while mTOR activates oncogenes. For example, class I PI3K and Akt switch it off [ 80 ].

Besides, p53 and Death-associated protein kinase DAPK are associated with human malignant growth and control autophagy [ 81 ]. The cell oncogenes Bcl-2 and Bcl-XL are frequently upregulated in human diseases and repress autophagy by inhibiting Beclin Besides, p62 overexpression via autophagy-lysosome promotes carcinogenesis via NF-κB flagging liberation, activating nuclear factor E2-related factor Nrf-2 , inducing ROS production, and leading to DNA damage.

The contrast between these paradoxical features of autophagy makes the association with disease treatment more complex. Notwithstanding, it has been recommended that in the initial phases of malignant growth, quality control via autophagy, especially over genome upkeep, suppresses carcinogenesis.

Autophagy might organize the support or passage of cells into the G0 stage and subsequently forestall the unconstrained proliferation of tumor cells.

Conversely, autophagy might provide nutrition for cancer cells and assist their growth when suffering from metabolic pressure and oppose passing set off by chemotherapeutics [ 82 ].

Furthermore, autophagy promotes growth cell endurance in normal and cancer cells. Although autophagy can postpone apoptosis, cell passing ultimately restricts autophagy. Apoptosis ordinarily escapes growing cells, granting supported endurance, movement, and protection from treatment.

The delayed pressure endurance managed by imperfect apoptosis occurs in cancer cells by either increased anti-apoptotic genes Bcl-2 and Bcl-xL or deficiency in pro-apoptotic genes Bax and Bak [ 83 ].

The shortfall of cell passing is insufficient to support the pressure endurance of growing cells. Thus, the pressure from glucose oxygen deprivation strongly enacts autophagy, upholding apoptotic cells' long-term endurance. Cancer cells evading apoptosis can also obtain nutrition via autophagy when they endure pressure for a long time and enter a torpid condition.

They can leave torpidity to continue cell multiplication when the pressure is released and typical development conditions are reestablished [ 84 ]. Hereditary or pharmacologic concealment of autophagy advances cell demise by putrefaction in vitro and in vivo, which suggests that growing and quiescent cells use autophagy to keep up with endurance in distressing conditions [ 85 ].

Autophagy limits these hypoxic districts, where it upholds growing cell endurance. Oxygen-detecting hypoxia-inducible factors activate autophagy alongside other metabolic factors and favor angiogenesis pathways unaffected by cell variation to metabolic pressure.

Autophagy induction in hypoxic areas might also hamper treatment due to proliferative cells that are resistant to treatment in these hypoxic areas. Hence, determining the cancer cell torpidity and recovery component and how to target this pathway to build novel anti-cancer strategies is essential.

Currently, lysosomotropism specialists e. On the other hand, autophagy can also effectively exhibit antitumor activity in some contexts, especially in focused growth cells or when blended with restorative mTOR hindrance. In this case, autophagy might improve endurance, conceivably subverting treatment.

Besides, various strategies using 3-MA, chloroquine, or hereditary manipulation of autophagy-related genes have shown that autophagy hindrance might sharpen growing cells to death, acting on assorted cytotoxic specialists [ 87 ].

Moreover, proteasome inhibitors can effectively trigger autophagy. Mechanistically, proteins can be degraded via two classical pathways: autophagy—lysosomal and ubiquitin—proteasome pathways. Inhibiting the ubiquitin—proteasome pathway activates the autophagy—lysosomal pathway.

For example, Bortezomib an FDA-approved proteasome inhibitor effectively enhances autophagy in colorectal cancer and myeloma cells [ 89 , 90 ].

Consistently, proteasome hindrance in prostate malignant growing cells by NPI can act through autophagy by an eIF2α-subordinate component that controls ATG function [ 91 ]. The concurrent inhibition of the two systems can result in a more effective strategy against cancer cells than the restraint of either pathway alone, which should be tested in the future.

In summary, this review provided a profound understanding of the relationship between inflammation and autophagy in various human disorders. Autophagy can assume fundamental roles in inflammatory diseases, infections, and carcinogenesis. A better comprehension of autophagy in different diseases has promising effects on developing improved treatments.

Meanwhile, autophagy studies are still being conducted, although their relevance to digestion, stress reaction, and cell demise pathways is recognized.

Consequently, this cycle and their related reactions might provide data on how the host reacts to exogenous microorganisms and endogenous particles created under pressure conditions, yet these occasions can be re-molded by different stimuli and cell types.

Altogether, understanding how autophagy is regulated and directed, and the particularity related to cell utilization, requires further examination.

It will be essential to characterize and portray sub-atomic and biochemical features associated with the intricate exchange among autophagy and different pathologies to advance novel approaches for patients with neurodegenerative diseases and infections.

The field of autophagy in immunity and inflammation-related diseases continues to evolve in both fundamental and translational fields.

In general, almost all human diseases possess an inflammatory component, which in turn provides a window of opportunity and a challenge to develop autophagy-based therapeutic strategies.

Considering the irreplaceable role of autophagy in the removal of the primary toxic entity causing disease and subsequently reducing the susceptibility to pro-death insults, which implying autophagy is a promising target mechanism from a therapeutic perspective.

Finally, various pre-clinical and clinical studies are needed to investigate the function of autophagy in several diseases. Münz C. Enhancing immunity through autophagy. Annu Rev Immunol. Article CAS PubMed Google Scholar. Virgin HW, Levine B.

Autophagy genes in immunity. Nat Immunol. Article CAS PubMed PubMed Central Google Scholar. Autophagy and autophagy-related proteins in cancer. Mol Cancer. Xiang H, Zhang J, Lin C, Zhang L, Liu B, Ouyang L. Targeting autophagy-related protein kinases for potential therapeutic purpose.

Acta Pharm Sin B. Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cybulsky AV. Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases.

Nat Rev Nephrol. Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ.

Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. Broz P, Dixit VM.

Inflammasomes: mechanism of assembly, regulation and signalling. Li W, He P, Huang Y, Li YF, Lu J, Li M, et al.

Selective autophagy of intracellular organelles: recent research advances. Deretic V. Autophagy in inflammation, infection, and immunometabolism. Racanelli AC, Kikkers SA, Choi AMK, Cloonan SM. Autophagy and inflammation in chronic respiratory disease.

Article PubMed PubMed Central Google Scholar. Matsuzawa-Ishimoto Y, Hwang S, Cadwell K. Autophagy and Inflammation. Wen JH, Li DY, Liang S, Yang C, Tang JX, Liu HF. Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis.

Front Immunol. Liu T, Wang L, Liang P, Wang X, Liu Y, Cai J, et al. USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy.

Cell Mol Immunol. Sanjurjo L, Aran G, Téllez É, Amézaga N, Armengol C, López D, et al. CD5L promotes M2 macrophage polarization through autophagy-mediated upregulation of ID3. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms.

J Pathol. Kerr JS, Adriaanse BA, Greig NH, Mattson MP, Cader MZ, Bohr VA, et al. Trends Neurosci. Lou G, Palikaras K, Lautrup S, Scheibye-Knudsen M, Tavernarakis N, Fang EF.

Mitophagy and neuroprotection. Trends Mol Med. Monkkonen T, Debnath J. Inflammatory signaling cascades and autophagy in cancer.

Gonzalez CD, Resnik R, Vaccaro MI. Secretory autophagy and its relevance in metabolic and degenerative disease. Front Endocrinol Lausanne. Article PubMed Google Scholar. Bustos SO, Leal Santos N, Chammas R, Andrade LNS. Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma.

Cancers Basel. Kraya AA, Piao S, Xu X, Zhang G, Herlyn M, Gimotty P, et al. Identification of secreted proteins that reflect autophagy dynamics within tumor cells. Autophagy: an emerging immunological paradigm. J Immunol. Atg7 deficiency intensifies inflammasome activation and pyroptosis in pseudomonas sepsis.

Li Q, Li L, Fei X, Zhang Y, Qi C, Hua S, et al. Inhibition of autophagy with 3-methyladenine is protective in a lethal model of murine endotoxemia and polymicrobial sepsis.

Innate Immun. Castillo EF, Dekonenko A, Arko-Mensah J, Mandell MA, Dupont N, Jiang S, et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation.

Proc Natl Acad Sci USA. Autophagy in the pathogenesis of disease. Arroyo DS, Gaviglio EA, Peralta Ramos JM, Bussi C, Rodriguez-Galan MC, Iribarren P.

Autophagy in inflammation, infection, neurodegeneration and cancer. Int Immunopharmacol. Xiao Y, Cai W. Autophagy and bacterial infection.

Adv Exp Med Biol. Onorati AV, Dyczynski M, Ojha R, Amaravadi RK. Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells.

Nat Cell Biol. Li W, Li Y, Siraj S, Jin H, Fan Y, Yang X, et al. FUN14 domain-containing 1-mediated mitophagy suppresses hepatocarcinogenesis by inhibition of inflammasome activation in mice. Chen D, Xie J, Fiskesund R, Dong W, Liang X, Lv J, et al. Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype.

Nat Commun. DeVorkin L, Pavey N, Carleton G, Comber A, Ho C, Lim J, et al. UA inhibits mitochondrial fission, restores mitochondrial fusion and reduces the proportion of mitochondrial fragments in endothelial cells. UA enhances mitochondrial biogenesis in endothelial cells by upregulating Sirtuin 3 and peroxisome proliferator-activated receptor γ coactivator 1-α [ 81 ].

In endothelial cells, autophagy can upregulate angiogenic activity and contribute to the repair of damaged endothelial cells by inducing prolonged hypoxia [ 82 ]. Mouse experiments also confirmed that autophagy activation can stimulate cell proliferation and regeneration near ischemic focal points.

Inflammation occurs mainly through the innate immune system using pattern recognition receptors. Toll-like and Nod-like receptors recognize exogenous or endogenous ligands and are activated, and a multiprotein signal transduction cascade is subsequently induced to promote the secretion of pro-inflammatory cytokines.

Inflammatory responses are associated with myocardial ischemia, reperfusion injury, septic cardiomyopathy, diabetic cardiomyopathy and heart failure. When myocardial injury occurs, organelles, microorganisms and a large number of damaged substances accumulate in cells Figure 1.

Autophagy regulates the inflammatory microenvironment and inhibits the inflammatory response through the clearance of cellular debris [ 83 ]. However, autophagy can promote the occurrence of the inflammatory response [ 84 ].

Therefore, autophagy has a bidirectional effect and methods for regulating the inflammatory microenvironment during myocardial injury have not been determined. However, it is well known that autophagy and inflammation are closely associated with myocardial injury.

Myocardial ischemia is the pathological state of coronary artery lumen occlusion or stenosis in coronary heart disease, which is characterized by limited blood supply to the heart.

During the state of myocardial ischemia, the lack of raw materials leads to a decrease in ATP synthesis, which induces autophagy to clear apoptotic cardiomyocytes, misfolded proteins and necrotic mitochondria and regulates the myocardial inflammatory microenvironment [ 85 ].

Protecting cardiomyocytes is a vital strategy for the treatment of acute MI. The infiltration of immune cells has been observed in border areas after acute MI, indicating suppression of the inflammatory reaction in ischemic cardiac regions [ 86 ].

It was found that inflammatory factors and autophagy signals were strongest during the first week and apoptotic signals peaked during the second week after ligation of the left coronary artery, and the increased level persisted until the fourth week [ 87 ].

The application of a TNF-α inhibitor significantly inhibited autophagy and promoted muscle cell apoptosis in the boundary region. These results suggest that the inflammatory response may play a protective role in early MI by stimulating autophagy in myocardial cells. Myocardial-associated transcription factor A MRTF-A exerts an inhibitory effect on MI.

Zhong et al. found that MRTF-A reduced the activity of the NLRP3 inflammasome and significantly increased the expression of autophagy proteins in ischemic myocardial tissue.

Lipopolysaccharide and 3-methyladenine 3-MA abrogated the protective effect of MRTF-A. Overexpression of MRTF-A and SIRT1 effectively reduced myocardial ischemia injury.

This outcome was related to a decrease in inflammatory cytokine levels and an increase in autophagy-related protein levels. The inhibition of SIRT1 activity partially suppressed the cardiac protective effect induced by MRTF-A [ 88 ].

Superoxide dismutase 1 SOD1 -KO mice showed excessive oxidative stress after AMI, which was caused by increased apoptosis of ischemic cardiomyocytes and an inflammatory response. In contrast, enhanced autophagy played a protective role.

SOD1-KO mice had more severe myocardial inflammation after AMI than wild-type mice [ 89 ]. Vitamin D deficiency is associated with AMI [ 89 ]. A study found that vitamin D3 treatment enhanced the expression of LC3II and Beclin-1, reduced levels of inflammatory cell infiltration and the MI size in AMI mice, and decreased levels of inflammatory factors and MI markers, significantly alleviating AMI-induced myocardial cell apoptosis.

Moreover, Bcl-2 upregulates or downregulates cysteine aspartic acid specific protease 3 caspase-3 , caspase-9 and Bax expression. In addition, vitamin D3 enhanced the inhibition of PI3K, P-Akt and P-mTOR expression induced by AMI [ 65 ]. The above experiments suggest that the pathway can promote autophagy in AMI-injured myocardium, protect against myocardial injury, inhibit the inflammatory response and improve the myocardial microenvironment.

Autophagy is closely related to the regulation of the inflammatory response to reperfusion injury after myocardial ischemia. Reperfusion injury is mainly due to acute injury caused by oxidative stress, which leads to ROS production after cardiomyocytes restore blood perfusion, and autophagy can reduce oxidative stress [ 90 ].

At present, the effect of autophagy on myocardial injury remains unclear and further exploration is needed. Overall, the inflammatory environment promotes cell death during ischemia, whereas autophagy controls inflammation and protects myocardial function by inhibiting inflammasome activation.

However, prolonged excessive autophagy may lead to the opposite effect by damaging cardiomyocytes. Autophagy and the myocardial inflammatory environment jointly regulate the entire process of myocardial ischemia. Sepsis is a systemic inflammatory syndrome caused by infection that further develops into multiple organ dysfunction syndrome.

The heart is one of the most vulnerable target organs. Many patients with severe sepsis have a decreased LVEF [ 92 ]. Improving the myocardial inflammatory microenvironment may represent a bottleneck in the treatment of sepsis.

In a mouse model of CLP sepsis, Hsieh et al. Electron microscopy confirmed that autophagic flow was blocked during the late stage of sepsis, which manifested as an increase in the formation of autophagosomes in the left ventricle.

However, reductions in their fusion with lysosomes hindered the degradation of autophagosomes, and the aggregation of autophagosomes promoted cardiac dysfunction and exacerbated septic cardiomyopathy. Busch et al. Further studies showed that IL-1β activated NF-κB and its target genes, resulting in myocyte myosin protein atrophy and reduction, which was accompanied by increased autophagy gene expression.

Activation of the NLRP3 inflammasome induces cleavage of caspase-1 and IL-1β precursors into mature forms and their release, inducing downstream immune signaling responses. Autophagy can clear NLRP3 inflammasome activators, such as intracellular blockers, reducing the inflammatory response [ 95 ].

When insufficiencies in autophagy result in failure to clear damaged mitochondria, they accumulate in the cell and cause oxidative stress. Excessive ROS can activate downstream pathways to produce cascading inflammatory effects and worsen the inflammatory microenvironment.

Mitochondria exist in a dynamic equilibrium state in which slightly damaged mitochondria can be repaired and complementarily fused with other damaged mitochondria into new mitochondria.

Mitochondria that cannot be repaired are degraded by lysosomes [ 96 ]. During the pathological process of SIC, excessive ROS lead to oxidative stress and mitochondrial DNA damage as well as impaired mitochondrial protein synthesis and respiratory function.

If damaged mitochondria are cleared by autophagy, mitochondrial biosynthesis is activated, which can alleviate myocardial injury caused by inflammation [ 97 ].

The process of septic cardiomyopathy is always accompanied by inflammation. Local pathological sections often exhibit inflammatory cell infiltration and deterioration of the inflammatory microenvironment. The mitochondrial structure and function of myocardial cells are damaged and mitochondrial autophagy is insufficient to clear damaged mitochondria.

These damaged mitochondria accumulate in the cell and cause oxidative stress, induce the production of a large number of ROS and promote the inflammatory cascade reaction [ 98 ]. A large number of cardiomyocytes with morphological characteristics similar to pyroptotic cells were observed in the SIC animal model, and the presence of these cells was closely related to the inflammatory microenvironment.

Autophagy can improve the inflammatory microenvironment by removing damaged DNA fragments, broken cell membranes, swollen organelles and cytoplasm. Diabetic cardiomyopathy is one of the most important causes of death in patients with diabetes mellitus. Its pathological features mainly include structural and functional damage, including myocardial cell metabolism disorder, insulin resistance, oxidative stress, inflammatory response and neuroendocrine system disorders.

The pathogenesis of diabetic cardiomyopathy myocardial injury remains unclear, but among many factors, the inflammatory response may play the most important role in promoting diabetic cardiomyopathy progression [ 99 ].

Typical autophagy is inhibited in type 1 diabetic hearts, and the reduction in autophagy is an adaptive change in type 1 diabetes that has a certain protective effect on cardiomyocytes [ ]. Diabetes-induced heart injury was significantly weakened in Beclin 1- and ATGdeficient diabetic mouse models [ ].

These mice exhibited improved heart function and reduced levels of oxidative stress, interstitial fibrosis and myocardial cell apoptosis.

In contrast, diabetic cardiac damage dose-dependently exacerbated Beclin 1 overexpression. These results suggest that reduced autophagy may represent an adaptive response to limit cardiac dysfunction in type 1 diabetes, possibly through upregulation of selective autophagy.

Fenofibrate FF is a peroxisome proliferator-activated receptor α agonist that has reduced lipid levels in the clinic, and 3-MA or sirtinol has eliminated the preventive effect of FF on high-glucose production. These results suggest that FF may prevent the myocardial inflammatory response and dysfunction induced by type 1 diabetes by increasing FGF21 levels, which may upregulate SIRT1-mediated autophagy.

In type 2 diabetes induced by a high-fat diet, increased activation of typical autophagy has a protective effect on the myocardium. However, in type 2 diabetes induced by fructose and milk fat, increased activation of typical autophagy may aggravate myocardial injury [ ].

One study observed increased expression of the cardiac autophagy marker LC3B-II and its mediator Beclin-1 and decreased expression of P62 in patients with type 2 diabetes. P62 was integrated into autophagosomes for effective degradation and promoted significant activation of apoptotic caspase These results suggest that increased autophagy activity occurs in type 2 diabetic hearts.

Cardiovascular toxicity caused by chemotherapy drugs has been increasingly recognized as an important factor affecting the survival and prognosis of cancer patients. The cardiotoxicity of anthracyclines is progressive and irreversible, with most symptoms appearing within 1 year of chemotherapy.

The process of chemotherapy-related cardiomyopathy is always accompanied by inflammation, and both systemic and local inflammatory reactions occur. The systemic inflammatory response mainly occurs during the end stage of heart failure, whereas the local inflammatory response is a key factor in the process of heart failure that undergoes various adaptive compensatory mechanisms until decompensation and ultimately changes in myocardial structure, function and phenotype occur [ ].

A recent study found that the IL-1 β concentration was positively associated with heart failure mortality. In addition, early heart failure was accompanied by elevated levels of inflammatory molecules and altered expression of genes involved in innate immunity, suggesting that inflammation and the innate immune system may represent an early response of cardiomyocytes to injury [ ].

Ma et al. In contrast, blocking TLR4 did not produce a similar phenomenon. Further studies showed that by disrupting the interaction between TLR2 and its endogenous ligand, the levels of inflammation and fibrosis in cardiomyocytes were reduced.

However, inhibition of TLR4 exacerbates cardiac dysfunction and myocardial fibrosis by amplifying inflammation and inhibiting autophagy. These results suggest that autophagy interacts with TLR2 and TLR4 and plays different roles in chemotherapy-related cardiomyopathy. In addition to attention focused on its established fundamental role in maintaining normal cellular phenotype and function, interest in how targeted modulation of autophagy can prevent myocardial injury has increased.

The use of autophagy as a therapeutic modality has gained widespread support in recent years. Studies have found that autophagy regulators, including rapamycin [ ], sulfaphenazole [ ], UTP [ ] and ranolazine [ 25 ] can reduce the myocardial infarct area, improve cardiac function and protect against myocardial ischemia.

Rapamycin has been shown to reduce cardiomyocyte apoptosis and promote cardiomyocyte autophagy by modulating the crosstalk of mTOR and endoplasmic reticulum stress pathway components in the chronic heart failure context [ ]. Rapamycin treatment of the myocardium significantly reduced the myocardial cell apoptosis rate, reduced the myocardial infarct area and enhanced cardiac function in mice after MI [ ].

Met, one of the most widely used drugs for the treatment of type 2 diabetes, has also shown cardiovascular protective activity.

Met enhanced autophagic flux and increased the regeneration of epicardium, endocardium and vascular endothelium [ ]. An important study found that the use of chloroquine was associated with increased cardiac risk in patients with COVID [ ]. In conclusion, autophagy is considered as a potential therapeutic modality, however, some challenges remain.

Myocardial injury is a dynamic process. The regulation of autophagy in myocardial injury is not static and needs to be maintained in a balanced state. In most cases, clearly, the use of autophagy regulators in the treatment of myocardial injury shows considerable potential.

Myocardial injury is a leading cause of morbidity and mortality worldwide. The cellular inflammatory response is closely related to the progression of myocardial injury.

A complex relationship exists between autophagy and immune cells. Numerous studies have confirmed that autophagy is involved in regulating inflammatory responses, including the digestion of apoptotic necrotic cells, damage to organelles and macromolecules to inhibit excessive inflammatory responses to improve the microenvironment, and the promotion of inflammatory responses to repair tissues.

The cell induces autophagy, clears inflammatory protein aggregates and downregulates the expression of pro-inflammatory cytokines produced during tissue damage to fight and improve the inflammatory response. Of note, the role of autophagy in regulating the inflammatory microenvironment of the myocardium is not absolute but is associated with changes in disease status.

In-depth exploration of the functions and mechanisms of autophagy in human health and disease will provide new opportunities and approaches to develop methods for the prevention and treatment of inflammation and immune-related diseases. This work was supported by the National Natural Science Foundation of China and , Shenzhen Fundamental Research Program No.

SGDX , Science and Technology Development Fund, Macau SAR No. MYRGICMS , Macao Youth Scholars Program AM , Guangdong Basic and Applied Basic Research Foundation A and A , Science and Technology Foundation of Guangzhou City , State Key Laboratory of Dampness Syndrome of Chinese Medicine Research Foundation SZZZ21 and SZQN02 , Scientific Research Projects of Guangdong Bureau of Traditional Chinese Medicine Nos.

CPL wrote the main article. YL drew the artwork. HC proofread the manuscript. XY was responsible for the insertion of the literature, and CJL, LW and JL were responsible for writing instructions and embellishing the text.

All authors contributed to the article and approved the submitted version. Roth GA , Mensah GA , Johnson CO , Addolorato G , Ammirati E , Baddour LM , et al. Global burden of cardiovascular diseases and risk factors, update from the GBD study.

J Am Coll Cardiol. Google Scholar. PCSK9 inhibition: from current advances to evolving future. Autophagy and myocardial ischemia. Adv Exp Med Biol. Therapeutic applications of extracellular vesicles for myocardial repair.

Front Cardiovasc Med. Designer functional Nanomedicine for myocardial repair by regulating the inflammatory microenvironment. Dillmann WH. Diabetic cardiomyopathy.

Circ Res. Higgins AY , O'Halloran TD , Chang JD. Chemotherapy-induced cardiomyopathy. Heart Fail Rev. Pathophysiology of sepsis-induced myocardial dysfunction. Mil Med Res. Jefferies JL , Towbin JA.

Dilated cardiomyopathy. McComb S , Thiriot A , Akache B , Krishnan L , Stark F. Introduction to the immune system. Methods Mol Biol.

A double-edged sword of immuno-microenvironment in cardiac homeostasis and injury repair. Signal Transduct Target Ther. Bento CF , Renna M , Ghislat G , Puri C , Ashkenazi A , Vicinanza M , et al.

Mammalian autophagy: how does it work? Annu Rev Biochem. Danlou tablets inhibit atherosclerosis in Apolipoprotein E-deficient mice by inducing macrophage autophagy: the role of the PI3K-Akt-mTOR pathway. Front Pharmacol. Gerada C , Ryan KM. Autophagy, the innate immune response and cancer.

Mol Oncol. Levine B , Mizushima N , Virgin HW. Autophagy in immunity and inflammation. Yang Z , Goronzy JJ , Weyand CM. Autophagy in autoimmune disease. J Mol Med Berl. Mizushima N , Komatsu M. Autophagy: renovation of cells and tissues. Yang Z , Klionsky DJ. An overview of the molecular mechanism of autophagy.

Curr Top Microbiol Immunol. Yu L , Chen Y , Tooze SA. Autophagy pathway: cellular and molecular mechanisms. Heckmann BL , Green DR. LC3-associated phagocytosis at a glance. J Cell Sci. Boya P , Reggiori F , Codogno P. Emerging regulation and functions of autophagy.

Nat Cell Biol. Amaravadi R , Kimmelman AC , White E. Recent insights into the function of autophagy in cancer. Genes Dev. Mizushima N , Levine B. Autophagy in human diseases. N Engl J Med. Tanida I. Autophagy basics. Microbiol Immunol.

Hale SL , Kloner RA. Ranolazine treatment for myocardial infarction? Effects on the development of necrosis, left ventricular function and arrhythmias in experimental models.

Cardiovasc Drugs Ther. Chanson M , Derouette JP , Roth I , Foglia B , Scerri I , Dudez T , et al. Gap junctional communication in tissue inflammation and repair. Entman ML , Youker K , Shoji T , Kukielka G , Shappell SB , Taylor AA , et al. Neutrophil induced oxidative injury of cardiac myocytes.

J Clin Invest. Kluever AK , Deindl E. Curr Pharm Biotechnol. Cohn JN , Ferrari R , Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling.

Behalf of an international forum on cardiac Remodeling. White HD , Norris RM , Brown MA , Brandt PW , Whitlock RM , Wild CJ.

Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Briaud SA , Ding ZM , Michael LH , Entman ML , Daniel S , Ballantyne CM.

Am J Physiol Heart Circ Physiol. Endogenous IRAK-M attenuates postinfarction remodeling through effects on macrophages and fibroblasts. Arterioscler Thromb Vasc Biol. Ong SB , Hernandez-Resendiz S , Crespo-Avilan GE , Mukhametshina RT , Kwek XY , Cabrera-Fuentes HA , et al.

Inflammation following acute myocardial infarction: multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol Ther.

Autophagy suppresses toll-like receptor 3-mediated inflammatory reaction in human epidermal keratinocytes.

Biomed Res Int. Mihalache CC , Simon HU.

Amd is a highly inflam,ation bulk degradation mechanism that degrades damaged organelles, aged Muscle growth workout strategies and intracellular contents to maintain the homeostasis anc the intracellular microenvironment. Activation of autophagy can be observed Autophagy and inflammation myocardial Autophagy and inflammation, ajd which inflammatory responses are strongly triggered. Autophagy can inhibit the inflammatory response and regulate the inflammatory microenvironment by removing invading pathogens and damaged mitochondria. In addition, autophagy may enhance the clearance of apoptotic and necrotic cells to promote the repair of damaged tissue. Briefly reviews the crosstalk between autophagy and inflammation in myocardial injury. Discusses the molecular mechanism of autophagy in regulating the inflammatory response in different cell types of myocardial injury.

Author: Gujora

0 thoughts on “Autophagy and inflammation

Leave a comment

Yours email will be published. Important fields a marked *

Design by ThemesDNA.com