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      Autophagy proteins regulate innate immune response by inhibiting NALP3 inflammasome-mediated mitochondrial DNA release

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          Abstract

          Autophagy, a cellular process for organelle and protein turnover, regulates innate immune responses. We demonstrate that depletion of autophagic proteins microtubule associated protein-1 light chain 3B (LC3B) and Beclin 1 enhances caspase-1 activation and secretion of interleukin-1β and interleukin-18. Autophagic protein depletion promoted accumulation of dysfunctional mitochondria and cytosolic translocation of mitochondrial DNA (mtDNA) in response to lipopolysaccharide (LPS) and ATP in macrophages. Release of mtDNA into the cytosol depended on the NALP3 inflammasome and mitochondrial ROS. Cytosolic mtDNA contributed to IL-1β and IL-18 secretion in response to LPS and ATP. LC3B-deficient mice produced more caspase-1-dependent cytokines in two sepsis models and were susceptible to LPS-induced mortality. Our study suggests that autophagic proteins regulate NALP3-dependent inflammation by preserving mitochondrial integrity.

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          Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.

          Tatsuya Saitoh, Naonobu Fujita, Myoung Ho Jang … (2008)
          Systems for protein degradation are essential for tight control of the inflammatory immune response. Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation. However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8, 9), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.
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            Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production.

            Nianyu Li, Kathy Ragheb, Gretchen Lawler … (2003)
            Inhibition of mitochondrial respiratory chain complex I by rotenone had been found to induce cell death in a variety of cells. However, the mechanism is still elusive. Because reactive oxygen species (ROS) play an important role in apoptosis and inhibition of mitochondrial respiratory chain complex I by rotenone was thought to be able to elevate mitochondrial ROS production, we investigated the relationship between rotenone-induced apoptosis and mitochondrial reactive oxygen species. Rotenone was able to induce mitochondrial complex I substrate-supported mitochondrial ROS production both in isolated mitochondria from HL-60 cells as well as in cultured cells. Rotenone-induced apoptosis was confirmed by DNA fragmentation, cytochrome c release, and caspase 3 activity. A quantitative correlation between rotenone-induced apoptosis and rotenone-induced mitochondrial ROS production was identified. Rotenone-induced apoptosis was inhibited by treatment with antioxidants (glutathione, N-acetylcysteine, and vitamin C). The role of rotenone-induced mitochondrial ROS in apoptosis was also confirmed by the finding that HT1080 cells overexpressing magnesium superoxide dismutase were more resistant to rotenone-induced apoptosis than control cells. These results suggest that rotenone is able to induce apoptosis via enhancing the amount of mitochondrial reactive oxygen species production.
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              Mitochondrial dynamics in mammalian health and disease.

              Marc Liesa, Manuel Palacín, Antonio Zorzano (2009)
              The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes (MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100941354
                Journal ID (pubmed-jr-id): 21750
                Journal ID (nlm-ta): Nat Immunol
                Title: Nature immunology
                ISSN (Print): 1529-2908
                ISSN (Electronic): 1529-2916
                Publication date Nihms-submitted: 20 December 2010
                Publication date (Electronic): 12 December 2010
                Publication date (Print): March 2011
                Publication date PMC-release: 1 September 2011
                Volume: 12
                Issue: 3
                Pages: 222-230
                Affiliations
                [1 ]Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
                [2 ]Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
                [3 ]The Wall Center for Pulmonary Vascular Diseases, School of Medicine, Stanford University, Stanford, CA, USA
                [4 ]School of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan, Korea
                Author notes

                AUTHOR CONTRIBUTIONS K.N., H.P.K., J.A.H and A.M.K.C conceived of the study with assistance from S.W.R. and K.A.F.; M.R. supervised the generation of LC3B-deficent mice; K.A.F. supervised the generation of AIM-2 deficient mice; K.N., S.J.L., and V.A.K.R did the in vitro experiments; J.A.H., S.J.L. and J.A.E. did the in vivo experiments; H.C.L. did TEM studies; M.C. and K.N. did FACS analysis; T.D. did analysis of human samples; K.N., J.A.H., A.M.K.C., and S.W.R. wrote the paper; A.M.K.C supervised the entire project.

                [† ]Correspondence should be addressed to A.M.K.C amchoi@ 123456rics.bwh.harvard.edu
                Article
                Manuscript ID: nihpa256871
                DOI: 10.1038/ni.1980
                PMC ID: 3079381
                PubMed ID: 21151103
                SO-VID: c61356f2-4ff8-4654-8a8d-51b2427a59ed
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL085547-02 ||HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL079904-12 ||HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL055330-14 ||HL
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Data availability:
                ScienceOpen disciplines: Immunology

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