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

被引：331

作者：

Mao, Kairui ^{[1
]}

Chen, Shuzhen ^{[1
]}

Chen, Mingkuan ^{[2
]}

Ma, Yonglei ^{[2
]}

Wang, Yan ^{[2
]}

Huang, Bo ^{[3
]}

He, Zhengyu ^{[4
]}

Zeng, Yan ^{[2
]}

Hu, Yu ^{[1
]}

Sun, Shuhui ^{[5
]}

Li, Jing ^{[6
]}

Wu, Xiaodong ^{[1
]}

Wang, Xiangrui ^{[4
]}

Strober, Warren ^{[7
]}

Chen, Chang ^{[3
]}

Meng, Guangxun ^{[2
]}

Sun, Bing ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200031, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai 200025, Peoples R China

[3] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China

[4] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Anesthesiol, Shanghai 200127, Peoples R China

[5] Fudan Univ, Sch Med, Shanghai 200032, Peoples R China

[6] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Informat Ctr Life Sci, Shanghai 200031, Peoples R China

[7] NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA

来源：

CELL RESEARCH | 2013年 / 23卷 / 02期

基金：

中国国家自然科学基金;

关键词：

nitric oxide; NLRP3; inflammasome; septic shock; NALP3; INFLAMMASOME; MESSENGER-RNA; SYNTHASE; CELLS; RECOGNITION; INHIBITORS; EXPRESSION; RESPONSES; DISEASE; NLRC4;

D O I：

10.1038/cr.2013.6

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Inflammasomes are multi-protein complexes that trigger the activation of caspase-1 and the maturation of interleukin-1 beta (IL-1 beta), 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-1 beta 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-1 beta 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.

引用

页码：201 / 212

页数：12

共 51 条

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