Key Points
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The cellular degradative process of autophagy participates in multiple aspects of immunity, including cell-autonomous defence, innate immune signalling and antigen presentation.
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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.
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Pathways that induce autophagy, such as those downstream of pattern recognition receptors, are conversely subject to regulation by autophagy.
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Autophagy can increase and decrease different components of the same inflammatory signalling cascade in a context-dependent manner.
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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.
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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.
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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
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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
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(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
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A multi-protein oligomer that catalyses the autoactivation of caspase 1, which cleaves pro-IL-1β and pro-IL-18 to produce the active forms of these cytokines.
- Pyroptosis
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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
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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 (CD5−) subsets.
- Citrullinated self-peptide
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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
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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
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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
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(Endoplasmic reticulum stress pathway). A conserved stress response pathway that senses the accumulation of unfolded proteins in the endoplasmic reticulum.
- Haematopoietic stem cell transplantation
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(HSCT). A procedure in which HSCs from bone marrow or blood are transplanted to treat leukaemia and other disorders.
- Graft-versus-host disease
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(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
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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.
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Cadwell, K. Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 16, 661–675 (2016). https://doi.org/10.1038/nri.2016.100
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DOI: https://doi.org/10.1038/nri.2016.100
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