Cutting edge: nitric oxide inhibits the NLRP3 inflammasome

• Published in: The Journal of immunology (1950) 2012-12, Vol.189 (11), p.5113-5117
• Main Authors: Hernandez-Cuellar, Eduardo, Tsuchiya, Kohsuke, Hara, Hideki, Fang, Rendong, Sakai, Shunsuke, Kawamura, Ikuo, Akira, Shizuo, Mitsuyama, Masao
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - pharmacology; Animals; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - immunology; Calcium-Binding Proteins - antagonists & inhibitors; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - immunology; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - immunology; Cells, Cultured; DNA-Binding Proteins; Female; Gene Expression Regulation - drug effects; Inflammasomes - drug effects; Inflammasomes - immunology; Interferon-beta - immunology; Interferon-beta - pharmacology; Lipopolysaccharides - pharmacology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - immunology; Mitochondria - metabolism; Nitric Oxide - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - immunology; Reactive Oxygen Species - metabolism; S-Nitroso-N-Acetylpenicillamine - metabolism; S-Nitroso-N-Acetylpenicillamine - pharmacology; Signal Transduction - drug effects; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1202479

Although the NLRP3 inflammasome plays a pivotal role in host defense, its uncontrolled activation is associated with inflammatory disorders, suggesting that regulation of the inflammasome is important to prevent detrimental effects. Type I IFNs and long-term LPS stimulation were shown to negatively regulate NLRP3 activation. In this study, we found that endogenous NO is involved in the regulation of NLRP3 inflammasome activation by either IFN-β pretreatment or long-term LPS stimulation. Furthermore, S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, markedly inhibited NLRP3 inflammasome activation, whereas the AIM2 and NLRC4 inflammasomes were only partially inhibited by SNAP. An increase in mitochondrial reactive oxygen species induced by ATP was only modestly affected by SNAP treatment. Interestingly, S-nitrosylation of NLRP3 was detected in macrophages treated with SNAP, and this modification may account for the NO-mediated mechanism controlling inflammasome activation. Taken together, these results revealed a novel role for NO in regulating the NLRP3 inflammasome.