Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock  

作　　者：Kairui Mao Shuzhen Chen Mingkuan Chen Yonglei Ma Yan Wang Bo Huang Zhengyu He Yan Zeng Yu Htl Shuhui Sun Jing Li Xiaodong Wu Xiangrui Wang Warren Strober Chang Chen Guangxun Meng Bing Sun 

机构地区：[1]State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chi-nese Academy of Sciences, Shanghai 200031, China [2]Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China [3]National Labora-tory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beo'ing 100101, China [4]Department of Anesthe-siology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China Fudan University School of Medicine, Shanghai 200032, China 6 Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China 7 Mucosal Immunity Section, Laboratory for Host Defenses, National In-stitute of Allergy and lnfectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA [5]Fudan University School of Medicine, Shanghai 200032, China [6]Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China [7]Mucosal Immunity Section, Laboratory for Host Defenses, National In-stitute of Allergy and lnfectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

出　　处：《Cell Research》2013年第2期201-212,共12页细胞研究（英文版）

基　　金：We thank R Caspi （National Eye Institute, NIH, USA） and D Li （Shanghai Institutes for Biological Sciences, China） for helpful comments, and S Skinner for critical reading of the manuscript. This work was supported by the National Basic Research Program of China （973 program, 2013CB530504）, the National Natural Science Foundation of China （31230024, 31030029, 31100662, 31030023, 91029707, 31170868）, the Shanghai Natural Science Foundation （11ZR1442600）, the National Ministry of Science and Technology （2007DFC31700）, the National Science and Technology Major Project （2008ZX10004-002, 2008ZX10002-014, 2009ZX10004-105, 2009ZXI0004-016, 2011ZX10004-001 and 2012ZXl0002007）, the Shanghai Pasteur Health Research Foundation （SPHRF2008001 and SPHRF2009001）, the SA-SIBS Discovery Innovation Grant, the Li Kha Shing Foundation and the 100 Talent Program of the Chinese Academy of Sciences （to GM）.

摘　　要：Inflammasomes are multi-protein complexes that trigger the activation of caspase-1 and the maturation of interleukin-1β （IL-1β）, yet the regulation of these complexes remains poorly characterized. Here we show that nitric oxide （NO） inhibited the NLRP3-mediated ASC pyroptosome formation, caspase-1 activation and IL-1β secretion in myeloid cells from both mice and humans. Meanwhile, endogenous NO derived from iNOS （inducible form of NO synthase） also negatively regulated NLRP3 inflammasome activation. Depletion of iNOS resulted in increased accu- mulation of dysfunctional mitochondria in response to LPS and ATP, which was responsible for the increased IL-1β production and caspase-1 activation, iNOS deficiency or pharmacological inhibition of NO production enhanced NL-RP3-dependent cytokine production in vivo, thus increasing mortality from LPS-induced sepsis in mice, which was prevented by NLRP3 deficiency. Our results thus identify NO as a critical negative regulator of the NLRP3 inflam-masome via the stabilization of mitochondria. This study has important implications for the design of new strategies to control NLRP3-related diseases.Inflammasomes are multi-protein complexes that trigger the activation of caspase-1 and the maturation of interleukin-1β （IL-1β）, yet the regulation of these complexes remains poorly characterized. Here we show that nitric oxide （NO） inhibited the NLRP3-mediated ASC pyroptosome formation, caspase-1 activation and IL-1β secretion in myeloid cells from both mice and humans. Meanwhile, endogenous NO derived from iNOS （inducible form of NO synthase） also negatively regulated NLRP3 inflammasome activation. Depletion of iNOS resulted in increased accu- mulation of dysfunctional mitochondria in response to LPS and ATP, which was responsible for the increased IL-1β production and caspase-1 activation, iNOS deficiency or pharmacological inhibition of NO production enhanced NL-RP3-dependent cytokine production in vivo, thus increasing mortality from LPS-induced sepsis in mice, which was prevented by NLRP3 deficiency. Our results thus identify NO as a critical negative regulator of the NLRP3 inflam-masome via the stabilization of mitochondria. This study has important implications for the design of new strategies to control NLRP3-related diseases.

关 键 词：nitric oxide NLRP3 inflammasome septic shock 

分 类 号：S852.3[农业科学—基础兽医学] Q539[农业科学—兽医学]