Key Points
-
The cellular degradative process of autophagy participates in multiple aspects of immunity, including cell-autonomous defence, innate immune signalling and antigen presentation.
-
Extensive crosstalk between autophagy and inflammatory signalling cascades ensures a robust immune response towards pathogens while avoiding collateral damage to the host. Several chronic inflammatory disorders are associated with autophagy dysfunction.
-
Pathways that induce autophagy, such as those downstream of pattern recognition receptors, are conversely subject to regulation by autophagy.
-
Autophagy can increase and decrease different components of the same inflammatory signalling cascade in a context-dependent manner.
-
Many immune-related functions of conserved autophagy proteins reflect non-canonical functions of the autophagy machinery, representing new opportunities for therapeutic intervention.
Abstract
Autophagy has broad functions in immunity, ranging from cell-autonomous defence to coordination of complex multicellular immune responses. The successful resolution of infection and avoidance of autoimmunity necessitates efficient and timely communication between autophagy and pathways that sense the immune environment. The recent literature indicates that a variety of immune mediators induce or repress autophagy. It is also becoming increasingly clear that immune signalling cascades are subject to regulation by autophagy, and that a return to homeostasis following a robust immune response is critically dependent on this pathway. Importantly, examples of non-canonical forms of autophagy in mediating immunity are pervasive. In this article, the progress in elucidating mechanisms of crosstalk between autophagy and inflammatory signalling cascades is reviewed. Improved mechanistic understanding of the autophagy machinery offers hope for treating infectious and inflammatory diseases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Macrophages in immunoregulation and therapeutics
Stenosing Crohnβs disease patients display gut autophagy/oxidative stress imbalance
References
Russell, R. C. et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15, 741β750 (2013).
Ge, L., Melville, D., Zhang, M. & Schekman, R. The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. eLife 2, e00947 (2013).
Hamasaki, M. et al. Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389β393 (2013).
Dooley, H. C. et al. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol. Cell 55, 238β252 (2014).
Randow, F. & Youle, R. J. Self and nonself: how autophagy targets mitochondria and bacteria. Cell Host Microbe 15, 403β411 (2014).
Choy, A. et al. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338, 1072β1076 (2012).This study provides an example of how intracellular bacteria block autophagy to evade trafficking to the lysosome.
Chen, Y. H. et al. Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell 160, 619β630 (2015).
Martinez, J. et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat. Cell Biol. 17, 893β906 (2015).This study demonstrates that LAP is distinguished from autophagy by its dependence on rubicon and NADPH oxidase 2 (NOX2).
Zhao, Z. et al. Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe 4, 458β469 (2008).
Hwang, S. et al. Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. Cell Host Microbe 11, 397β409 (2012).
Choi, J. et al. The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy. Immunity 40, 924β935 (2014).
Selleck, E. M. et al. A noncanonical autophagy pathway restricts Toxoplasma gondii growth in a strain-specific manner in IFN-Ξ³ activated human cells. mBio 6, e01157βe01115 (2015).
Ohshima, J. et al. Role of mouse and human autophagy proteins in IFN-Ξ³-induced cell-autonomous responses against Toxoplasma gondii. J. Immunol. 192, 3328β3335 (2014).
Haldar, A. K., Piro, A. S., Pilla, D. M., Yamamoto, M. & Coers, J. The E2-like conjugation enzyme Atg3 promotes binding of IRG and Gbp proteins to Chlamydia- and Toxoplasma-containing vacuoles and host resistance. PLoS ONE 9, e86684 (2014).
Park, S. et al. Targeting by Autophagy proteins (TAG): targeting of IFNΞ³-inducible GTPases to membranes by the LC3 conjugation system of autophagy. Autophagy 12, 1153β1167 (2016).
Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201β206 (2013).This study shows that a cell-permeable beclin 1 peptide induces autophagy to enhance host defence.
Orvedahl, A. et al. Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe 7, 115β127 (2010).
Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94β98 (2014).
Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135β1145 (2010).
Visvikis, O. et al. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. Immunity 40, 896β909 (2014).
Maurer, K. et al. Autophagy mediates tolerance to Staphylococcus aureus Ξ±-toxin. Cell Host Microbe 17, 429β440 (2015).This study shows that autophagy limits damage caused by a pore-forming toxin from a clinical isolate of S. aureus.
Figueiredo, N. et al. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity 39, 874β884 (2013).
Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936β941 (2012).
Marchiando, A. M. et al. A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe 14, 216β224 (2013).
Park, S. et al. Autophagy genes enhance murine gammaherpesvirus 68 reactivation from latency by preventing virus-induced systemic inflammation. Cell Host Microbe 19, 91β101 (2016).
Lu, Q. et al. Homeostatic control of innate lung inflammation by vici syndrome gene Epg5 and additional autophagy genes promotes influenza pathogenesis. Cell Host Microbe 19, 102β113 (2016).
Tattoli, I. et al. Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. Cell Host Microbe 11, 563β575 (2012).
Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1Ξ² production. Nature 456, 264β268 (2008).This study is the first to demonstrate the immunosuppressive function of autophagy in limiting inflammasome activation.
Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222β230 (2011).
Zhong, Z. et al. NF-ΞΊB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896β910 (2016).This study shows that mitophagy inhibits inflammasome activation in the presence of LPS.
Dupont, N. et al. Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy. Cell Host Microbe 6, 137β149 (2009).
Meunier, E. et al. Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases. Nature 509, 366β370 (2014).
Kreibich, S. et al. Autophagy proteins promote repair of endosomal membranes damaged by the Salmonella type three secretion system 1. Cell Host Microbe 18, 527β537 (2015).
Suzuki, T. et al. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 3, e111 (2007).
Byrne, B. G., Dubuisson, J. F., Joshi, A. D., Persson, J. J. & Swanson, M. S. Inflammasome components coordinate autophagy and pyroptosis as macrophage responses to infection. mBio 4, e00620β00612 (2013).
Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL-1Ξ² production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255β263 (2012).
Bodemann, B. O. et al. RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144, 253β267 (2011).
Ravindran, R. et al. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 531, 523β527 (2016).
Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045β1059 (2014).
Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11, 55β62 (2010).
Cooney, R. et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16, 90β97 (2010).
Homer, C. R. et al. A dual role for receptor-interacting protein kinase 2 (RIP2) kinase activity in nucleotide-binding oligomerization domain 2 (NOD2)-dependent autophagy. J. Biol. Chem. 287, 25565β25576 (2012).
Anand, P. K. et al. TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via extracellular signal-regulated kinase (ERK) activation. J. Biol. Chem. 286, 42981β42991 (2011).
Irving, A. T. et al. The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling. Cell Host Microbe 15, 623β635 (2014).
Chauhan, S., Mandell, M. A. & Deretic, V. IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol. Cell 58, 507β521 (2015).
Plantinga, T. S. et al. Crohn's disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2. Gut 60, 1229β1235 (2011).
Buffen, K. et al. Autophagy modulates Borrelia burgdorferi-induced production of interleukin-1Ξ² (IL-1Ξ²). J. Biol. Chem. 288, 8658β8666 (2013).
Lassen, K. G. et al. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc. Natl Acad. Sci. USA 111, 7741β7746 (2014).
Murthy, A. et al. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Nature 506, 456β462 (2014).
Lupfer, C. et al. Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat. Immunol. 14, 480β488 (2013).
Wen, Z. et al. Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation. J. Immunol. 193, 4623β4633 (2014).
Chu, H. et al. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352, 1116β1120 (2016).
Xu, Y. et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27, 135β144 (2007).
Delgado, M. A., Elmaoued, R. A., Davis, A. S., Kyei, G. & Deretic, V. Toll-like receptors control autophagy. EMBO J. 27, 1110β1121 (2008).
Shi, C. S. & Kehrl, J. H. TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagy. Sci. Signal. 3, ra42 (2010).
Meijer, A. H. & van der Vaart, M. DRAM1 promotes the targeting of mycobacteria to selective autophagy. Autophagy 10, 2389β2391 (2014).
Fujita, K., Maeda, D., Xiao, Q. & Srinivasula, S. M. Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation. Proc. Natl Acad. Sci. USA 108, 1427β1432 (2011).
Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228β233 (2011).
Moy, R. H. et al. Antiviral autophagy restricts Rift Valley fever virus infection and is conserved from flies to mammals. Immunity 40, 51β65 (2014).
Benjamin, J. L., Sumpter, R. Jr., Levine, B. & Hooper, L. V. Intestinal epithelial autophagy is essential for host defense against invasive bacteria. Cell Host Microbe 13, 723β734 (2013).
Lee, H. K., Lund, J. M., Ramanathan, B., Mizushima, N. & Iwasaki, A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315, 1398β1401 (2007).
Henault, J. et al. Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. Immunity 37, 986β997 (2012).
Sanjuan, M. A. et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253β1257 (2007).
Akoumianaki, T. et al. Aspergillus cell wall melanin blocks LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe 19, 79β90 (2016).
Katsuragi, Y. Ichimura, Y. & Komatsu, M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J. 282, 4672β4678 (2015).
Lee, H. M. et al. Autophagy negatively regulates keratinocyte inflammatory responses via scaffolding protein p62/SQSTM1. J. Immunol. 186, 1248β1258 (2011).
Kim, J. K. et al. MicroRNA-125a inhibits autophagy activation and antimicrobial responses during mycobacterial infection. J. Immunol. 194, 5355β5365 (2015).
Lei, Y. et al. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 36, 933β946 (2012).
Xia, M. et al. Mitophagy enhances oncolytic measles virus replication by mitigating DDX58/RIG-I-like receptor signaling. J. Virol. 88, 5152β5164 (2014).
Zhao, Y. et al. COX5B regulates MAVS-mediated antiviral signaling through interaction with ATG5 and repressing ROS production. PLoS Pathog. 8, e1003086 (2012).
Tal, M. C. et al. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc. Natl Acad. Sci. USA 106, 2770β2775 (2009).
Jounai, N. et al. The Atg5βAtg12 conjugate associates with innate antiviral immune responses. Proc. Natl Acad. Sci. USA 104, 14050β14055 (2007).
Saitoh, T. et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl Acad. Sci. USA 106, 20842β20846 (2009).
Konno, H., Konno, K. & Barber, G. N. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155, 688β698 (2013).
Liang, Q. et al. Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15, 228β238 (2014).
Lan, Y. Y., Londono, D., Bouley, R., Rooney, M. S. & Hacohen, N. Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep. 9, 180β119 (2014).
Mathew, R. et al. Functional role of autophagy-mediated proteome remodeling in cell survival signaling and innate immunity. Mol. Cell 55, 916β930 (2014).
Grimm, W. A. et al. The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon. Gut 65, 456β464 (2016).
Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753β766 (2004).
Harris, J. et al. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity 27, 505β517 (2007).
Mostowy, S. et al. p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways. J. Biol. Chem. 286, 26987β26995 (2011).
Matsuzawa, T. et al. IFN-Ξ³ elicits macrophage autophagy via the p38 MAPK signaling pathway. J. Immunol. 189, 813β818 (2012).
Chang, Y. P. et al. Autophagy facilitates IFN-Ξ³-induced Jak2-STAT1 activation and cellular inflammation. J. Biol. Chem. 285, 28715β28722 (2010).
Boonhok, R. et al. LAP-like process as an immune mechanism downstream of IFN-Ξ³ in control of the human malaria Plasmodium vivax liver stage. Proc. Natl Acad. Sci. USA 113, E3519βE3528 (2016).
Shen, S. et al. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol. Cell 48, 667β680 (2012).
Van Grol, J. et al. HIV-1 inhibits autophagy in bystander macrophage/monocytic cells through Src-Akt and STAT3. PLoS ONE 5, e11733 (2010).
Terawaki, S. et al. RUN and FYVE domain-containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4. J. Cell Biol. 210, 1133β1152 (2015).
Dupont, N. et al. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1Ξ². EMBO J. 30, 4701β4711 (2011).
Cullen, S. P., Kearney, C. J., Clancy, D. M. & Martin, S. J. Diverse activators of the NLRP3 inflammasome promote IL-1Ξ² secretion by triggering necrosis. Cell Rep. 11, 1535β1548 (2015).
Zhang, M., Kenny, S., Ge, L., Xu, K. & Schekman, R. Translocation of interleukin-1Ξ² into a vesicle intermediate in autophagy-mediated secretion. eLife 4, e11205 (2015).
Pilli, M. et al. TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity 37, 223β234 (2012).
Castillo, E. F. et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc. Natl Acad. Sci. USA 109, E3168βE3176 (2012).
Lee, J. P. et al. Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages. Autophagy 12, 907β916 (2016).
Peral de Castro, C. et al. Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion. J. Immunol. 189, 4144β4153 (2012).
Ding, Y. et al. Autophagy regulates TGF-Ξ² expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J. Am. Soc. Nephrol. 25, 2835β2846 (2014).
Trinchieri, G. Type I interferon: friend or foe? J. Exp. Med. 207, 2053β2063 (2010).
Mello Pde, A. et al. Adenosine uptake is the major effector of extracellular ATP toxicity in human cervical cancer cells. Mol. Biol. Cell 25, 2905β2918 (2014).
Biswas, D. et al. ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages. BMC Immunol. 9, 35 (2008).
Takenouchi, T. et al. The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells. J. Immunol. 182, 2051β2062 (2009).
Bian, S. et al. P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PLoS ONE 8, e60184 (2013).
Martins, I. et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 21, 79β91 (2014).
Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573β1577 (2011).This study demonstrates that autophagy promotes antitumour immunity by mediating the release of ATP.
Tang, D. et al. Endogenous HMGB1 regulates autophagy. J. Cell Biol. 190, 881β892 (2010).
Kang, R. et al. The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ. 17, 666β676 (2010).
Tang, D. et al. High-mobility group box 1 is essential for mitochondrial quality control. Cell. Metabolism 13, 701β711 (2011).
Zhu, X. et al. Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation. J. Clin. Invest. 125, 1098β1110 (2015).
Yanai, H. et al. Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. Proc. Natl Acad. Sci. USA 110, 20699β20704 (2013).
Pua, H. H., Dzhagalov, I., Chuck, M., Mizushima, N. & He, Y. W. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204, 25β31 (2007).This study is the first to demonstrate that deficiency in an autophagy protein leads to defects in lymphocyte survival and proliferation.
Stephenson, L. M. et al. Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T lymphocytes. Autophagy 5, 625β635 (2009).
Jia, W. & He, Y. W. Temporal regulation of intracellular organelle homeostasis in T lymphocytes by autophagy. J. Immunol. 186, 5313β5322 (2011).
Kovacs, J. R. et al. Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery. Cell Death Differ. 19, 144β152 (2012).
Pei, B. et al. Invariant NKT cells require autophagy to coordinate proliferation and survival signals during differentiation. J. Immunol. 194, 5872β5884 (2015).
Willinger, T. & Flavell, R. A. Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis. Proc. Natl Acad. Sci. USA 109, 8670β8675 (2012).
Matsuzawa, Y. et al. TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy. Autophagy 11, 1052β1062 (2015).
Xu, X. et al. Autophagy is essential for effector CD8+ T cell survival and memory formation. Nat. Immunol. 15, 1152β1161 (2014).
O'Sullivan, T. E., Johnson, L. R., Kang, H. H. & Sun, J. C. BNIP3- and BNIP3L-mediated mitophagy promotes the generation of natural killer cell memory. Immunity 43, 331β342 (2015).
Puleston, D. J. et al. Autophagy is a critical regulator of memory CD8+ T cell formation. eLife 3, e03706 (2014).
Schlie, K. et al. Survival of effector CD8+ T cells during influenza infection is dependent on autophagy. J. Immunol. 194, 4277β4286 (2015).
Henson, S. M. et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J. Clin. Invest. 124, 4004β4016 (2014).
Hubbard, V. M. et al. Macroautophagy regulates energy metabolism during effector T cell activation. J. Immunol. 185, 7349β7357 (2010).
Miller, B. C. et al. The autophagy gene ATG5 plays an essential role in B lymphocyte development. Autophagy 4, 309β314 (2008).
Conway, K. L. et al. ATG5 regulates plasma cell differentiation. Autophagy 9, 528β537 (2013).
Pengo, N. et al. Plasma cells require autophagy for sustainable immunoglobulin production. Nat. Immunol. 14, 298β305 (2013).
Paul, S., Kashyap, A. K., Jia, W., He, Y. W. & Schaefer, B. C. Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-ΞΊB. Immunity 36, 947β958 (2012).
Wei, J. et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17, 277β285 (2016).
Kabat, A. M. et al. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. eLife 5, de12444 (2016).
Dengjel, J. et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl Acad. Sci. USA 102, 7922β7927 (2005).
Nedjic, J., Aichinger, M., Emmerich, J., Mizushima, N. & Klein, L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455, 396β400 (2008).
Ireland, J. M. & Unanue, E. R. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J. Exp. Med. 208, 2625β2632 (2011).
Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593β596 (2005).
Lee, Y. et al. p62 plays a specific role in interferon-Ξ³-induced presentation of a Toxoplasma vacuolar antigen. Cell Rep. 13, 223β233 (2015).
Sakowski, E. T. et al. Ubiquilin 1 promotes IFN-Ξ³-induced xenophagy of Mycobacterium tuberculosis. PLoS Pathog. 11, e1005076 (2015).
Romao, S. et al. Autophagy proteins stabilize pathogen-containing phagosomes for prolonged MHC II antigen processing. J. Cell Biol. 203, 757β766 (2013).
Martinez, J. et al. Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc. Natl Acad. Sci. USA 108, 17396β17401 (2011).
Brooks, C. R. et al. KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation. EMBO J. 34, 2441β2464 (2015).
Lee, H. K. et al. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32, 227β239 (2010).This study demonstrates that the autophagy pathway in DCs is crucial for antigen presentation during herpesvirus infection in vivo.
Gobeil, P. A. & Leib, D. A. Herpes simplex virus gamma34.5 interferes with autophagosome maturation and antigen presentation in dendritic cells. mBio 3, e00267β00212 (2012).
Ravindran, R. et al. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science 343, 313β317 (2014).This study shows that autophagy induced by the nutrient sensor GCN2 promotes cross-presentation of viral antigens.
Jostins, L. et al. Hostβmicrobe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119β124 (2012).
Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259β263 (2008).This study identifies a role for the autophagy gene ATG16L1 in supporting intestinal Paneth cells.
Patel, K. K. et al. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production. EMBO J. 32, 3130β3144 (2013).
Adolph, T. E. et al. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272β276 (2013).
Conway, K. L. et al. Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 145, 1347β1357 (2013).
Hubbard-Lucey, V. M. et al. Autophagy gene atg16l1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41, 579β591 (2014).
Martin, L. J. et al. Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma. PLoS ONE 7, e33454 (2012).
Zhou, X. J. et al. Genetic association of PRDM1- ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population. Ann. Rheumat. Diseases 70, 1330β1337 (2011).
Dickinson, J. D. et al. IL13 activates autophagy to regulate secretion in airway epithelial cells. Autophagy 12, 397β409 (2015).
Clarke, A. J. et al. Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann. Rheumat. Diseases 74, 912β920 (2015).
Alessandri, C. et al. T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy. FASEB J. 26, 4722β4732 (2012).
Weindel, C. G. et al. B cell autophagy mediates TLR7-dependent autoimmunity and inflammation. Autophagy 11, 1010β1024 (2015).
Martinez, J. et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 533, 115β119 (2016).
Huang, J. et al. Activation of antibacterial autophagy by NADPH oxidases. Proc. Natl Acad. Sci. USA 106, 6226β6231 (2009).
De Luca, A. et al. CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease. J. Clin. Invest. 122, 1816β1831 (2012).
De Luca, A. et al. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc. Natl Acad. Sci. USA 111, 3526β3531 (2014).
Schwerd, T. et al. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. Gut http://dx.doi.org/10.1136/gutjnl-2015-310382 (2016).
Luciani, A. et al. Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat. Cell Biol. 12, 863β875 (2010).
Abdulrahman, B. A. et al. Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis. Autophagy 7, 1359β1370 (2011).
Renna, M. et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J. Clin. Invest. 121, 3554β3563 (2011).
Pyo, J. O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nature Commun. 4, 2300 (2013).
Starr, T. et al. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. Cell Host Microbe 11, 33β45 (2012).
Kimmey, J. M. et al. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature 528, 565β569 (2015).This study identifies a non-autophagy function of ATG5 in defence against M. tuberculosis.
Reggiori, F. et al. Coronaviruses hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe 7, 500β508 (2010).
Kageyama, S. et al. The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella. Mol. Biol. Cell 22, 2290β2300 (2011).
Sorbara, M. T. et al. The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner. Immunity 39, 858β873 (2013).
Liu, E., Van Grol, J. & Subauste, C. S. Atg5 but not Atg7 in dendritic cells enhances IL-2 and IFN-Ξ³ production by Toxoplasma gondii-reactive CD4+ T cells. Microbes Infect. 17, 275β284 (2015).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661β678 (2007).
Cullup, T. et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat. Genet. 45, 83β87 (2013).
Hakonarson, H. et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448, 591β594 (2007).
Soleimanpour, S. A. et al. The diabetes susceptibility gene Clec16a regulates mitophagy. Cell 157, 1577β1590 (2014).
Schuster, C. et al. The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection. Immunity 42, 942β952 (2015).
Smyth, D. J. et al. PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes. Diabetes 57, 1730β1737 (2008).
Martinez, A. et al. Chromosomal region 16p13: further evidence of increased predisposition to immune diseases. Ann. Rheumat. Diseases 69, 309β311 (2010).
Scharl, M. et al. Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflamm. Bowel Dis. 18, 900β912 (2012).
Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J. & Weyand, C. M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119β2134 (2013).
Acknowledgements
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. K.C. is supported by NIH grants DK103788, DK093668, HL123340, Stony Wold-Herbert Fund, and philanthropic support from Bernard Levine. K.C. is a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases.
Ethics declarations
Competing interests
The author declares no competing financial interests.
Glossary
- Autophagy
-
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.
- Xenophagy
-
A cell-intrinsic defence mechanism involving the selective degradation of microorganisms (such as bacteria, fungi, parasites and viruses) through an autophagy-related mechanism.
- Sequestosome 1
-
(SQSTM1). 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.
- Inflammasome
-
A multi-protein oligomer that catalyses the autoactivation of caspase 1, which cleaves pro-IL-1Ξ² and pro-IL-18 to produce the active forms of these cytokines.
- Pyroptosis
-
An inflammatory form of programmed cell death that is dependent on inflammasome-mediated activation of caspase 1.
- Outer membrane vesicles
-
(OMVs). Vesicles derived from the bacterial outer membrane that can be immunogenic and mediate interactions between commensal or pathogenic bacteria and the host.
- B1a B cells
-
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. B1 cells are subdivided into the B1a (CD5+) and B1b (CD5β) subsets.
- Citrullinated self-peptide
-
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.
- Cross-presentation
-
The initiation of a CD8+ T cell response to an antigen that is not present within antigen-presenting cells (APCs). This exogenous antigen must be taken up by APCs and then re-routed to the MHC class I pathway of antigen presentation.
- Crohn disease
-
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.
- ER stress pathway
-
(Endoplasmic reticulum stress pathway). A conserved stress response pathway that senses the accumulation of unfolded proteins in the endoplasmic reticulum.
- Haematopoietic stem cell transplantation
-
(HSCT). A procedure in which HSCs from bone marrow or blood are transplanted to treat leukaemia and other disorders.
- Graft-versus-host disease
-
(GVHD). A common complication of HSCT in which allogeneic T cells derived from a non-identical donor attack healthy tissue in the recipient.
- Chronic granulomatous disease
-
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.
Rights and permissions
About this article
Cite this article
Cadwell, K. Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 16, 661β675 (2016). https://doi.org/10.1038/nri.2016.100
Published:
Issue date:
DOI: https://doi.org/10.1038/nri.2016.100
Share this article
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
This article is cited by
-
Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice
Journal of Neuroinflammation (2024)
-
Selenomethionine Inhibits NF-ΞΊB-mediated Inflammatory Responses of Bovine Mammary Epithelial Cells Caused by Klebsiella pneumoniae by Increasing Autophagic Flux
Biological Trace Element Research (2024)
-
Reducing Nogo-B Improves Hepatic Fibrosis by Inhibiting BACe1-Mediated Autophagy
Tissue Engineering and Regenerative Medicine (2024)
-
Klotho enhances bone regenerative function of hPDLSCs via modulating immunoregulatory function and cell autophagy
Journal of Orthopaedic Surgery and Research (2023)
-
Role of macrophage autophagy in postoperative pain and inflammation in mice
Journal of Neuroinflammation (2023)
