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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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          Most cited references 52

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          Autophagy in the pathogenesis of disease.

          Autophagy is a lysosomal degradation pathway that is essential for survival, differentiation, development, and homeostasis. Autophagy principally serves an adaptive role to protect organisms against diverse pathologies, including infections, cancer, neurodegeneration, aging, and heart disease. However, in certain experimental disease settings, the self-cannibalistic or, paradoxically, even the prosurvival functions of autophagy may be deleterious. This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.
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            The inflammasomes.

            Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy. 2010 Elsevier Inc. All rights reserved.
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              Regulation mechanisms and signaling pathways of autophagy.

              Autophagy is a process of self-degradation of cellular components in which double-membrane autophagosomes sequester organelles or portions of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases. Autophagy is upregulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation, ER stress, and pathogen infection. Defective autophagy plays a significant role in human pathologies, including cancer, neurodegeneration, and infectious diseases. We present our current knowledge on the key genes composing the autophagy machinery in eukaryotes from yeast to mammalian cells and the signaling pathways that sense the status of different types of stress and induce autophagy for cell survival and homeostasis. We also review the recent advances on the molecular mechanisms that regulate the autophagy machinery at various levels, from transcriptional activation to post-translational protein modification.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nature immunology
                1529-2908
                1529-2916
                20 December 2010
                12 December 2010
                March 2011
                1 September 2011
                : 12
                : 3
                : 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
                nihpa256871
                10.1038/ni.1980
                3079381
                21151103

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                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
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                Immunology

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