Volume 23, No 2, Feb 2013
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 23 Issue 2, February 2013: 201-212
ORIGINAL ARTICLES
Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock
Kairui Mao1,*, Shuzhen Chen1,*, Mingkuan Chen2, Yonglei Ma2, Yan Wang2, Bo Huang3, Zhengyu He4, Yan Zeng2, Yu Hu1, Shuhui Sun5, Jing Li6, Xiaodong Wu1, Xiangrui Wang4, Warren Strober7, Chang Chen3, Guangxun Meng2 and Bing Sun1,2
1State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
2Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China
3National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
4Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
5Fudan University School of Medicine, Shanghai 200032, China
6Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
7Mucosal Immunity Section, Laboratory for Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Correspondence: Bing Sun, Guangxun Meng, Chang Chen(bsun@sibs.ac.cn; gxmeng@sibs.ac.cn; changchen@moon.ibp.ac.cn)
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 accumulation 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 NLRP3-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 inflammasome via the stabilization of mitochondria. This study has important implications for the design of new strategies to control NLRP3-related diseases.
Cell Research (2013) 23:201–212; doi:10.1038/cr.2013.6; published online 15 January 2013
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