Autophagy proteins regulate innate immune response by inhibiting NALP3 inflammasome-mediated mitochondrial DNA release
By K. Nakahira, J. Haspel, Vijay A. K. Rathinam, Seon-Jin Lee, T. Dolinay, H. Lam, J. Englert, M. Rabinovitch, M. Cernadas, Hong-pyo Kim and 3 more. Nature Immunology, 2010
2,779 citations recorded by the source corpus.
Autophagy, a cellular process for organelle and protein turnover, regulates innate immune responses. Here we demonstrate that depletion of the autophagic proteins LC3B and beclin 1 enhanced the activation of caspase-1 and secretion of interleukin 1β (IL-1β) and IL-18. Depletion of autophagic proteins promoted the 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 reactive oxygen species (ROS). Cytosolic mtDNA contributed to the secretion of IL-1β and IL-18 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.
Subfields: Epidemiology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/5232df542ed0595804496cc67609f2693c219daf
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Citations in the corpus
- Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation (2013, background): “Recent studies have elucidated the cellular source of the responsible ROS to be of mitochondrial origin and independent of the NADPH oxidases (Meissner et al., 2008; Nakahira et al., 2011; van Bruggen et al., 2010; Zhou et al., 2011).”
- Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation* (2012, background): “mtROS Are Required for Non-transcriptional Priming of NLRP3—mtROS have been implicated in regulation of the NLRP3 inflammasome (13, 14), but the mechanism is still unclear.”
- TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation (2012, neutral): “In the context of antiinflammatory function, autophagy plays an inhibitory role in inflammasome and IL-1b activation (Dupont et al., 2011; Nakahira et al., 2011; Zhou et al., 2011).”
- Mitophagy: mechanisms, pathophysiological roles, and analysis (2012, methodology): “Cytosolic mtDNA promotes the secretion of IL-1 β and IL-18 following stimulation with lipopolysaccharide or ATP (Nakahira et al. , 2011 ).”
- The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “found that mtROS generated from dysfunctional mitochondria is required for NLRP3 inflammasome activation in response to LPS and ATP, and mitochondrial DNA (mtDNA) is released into the cytosol in both an NLRP3- and mtROS-dependent manner [98].”
- Mitochondria in the regulation of innate and adaptive immunity (2015, neutral): “Apart frommitochondrial ROS, release of mitochondrial DNA (mtDNA) into the cytosol was found to enhance NLRP3 activation (Nakahira et al., 2011).”
- The Impact of Oxidative Stress and Inflammation on RPE Degeneration in Non-neovascular AMD (2017, background): “…after excess metabolism (Brunelle et al., 2005; Guzy et al., 2005), response to hypoxia via HIF-1α (Guzy et al., 2005), regulation of autophagy through ATF4 (Scherz-Shouval et al., 2007), and regulation of inflammatory responses (Bulua et al., 2011; Nakahira et al., 2011; Zhou et al., 2011).”
- Mitochondrial DNA in inflammation and immunity (2020, neutral): “Interest-ingly, Nakahira et al suggested that as well as acting downstream of mtDNA release, NLRP3 also acts upstream, to facilitate mPTP formation on the mitochondria allowing mtDNA release.”