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Chen, Q.* ; Zheng, J. ; Wang, D.* ; Liu, Q.* ; Kang, L.* ; Gao, X.* ; Lin, Z.*

Nitrosonisoldipine is a selective inhibitor of inflammatory caspases and protects against pyroptosis and related septic shock.

Eur. J. Immunol. 51, 1234-1245 (2021)
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Pyroptosis is a type of acute cell death that mainly occurs in immune cells. It is characterized with robust release of inflammatory cytokines and has emerged to play a critical role in the pathogenesis of sepsis-associated immune disorders. In this study, we screened for pyroptotic inhibitors with the ultimate goal to benefit sepsis treatments. Accidentally, we identified nitrosonisoldipine (NTS), a photodegradation product of calcium channel inhibitor nisoldipine, blocking non-canonical pyroptosis. Using murine immortalized bone-marrow derived macrophage and human THP-1 cell line, we further discovered that NTS not only inhibits non-canonical pyroptosis mediated by caspase-11 or caspase-4, but also canonical pyroptosis mediated by caspase-1. Mechanistically, NTS directly inhibits the enzyme activities of these inflammatory caspases, and these inhibitory effects persist despite extensive washout of the drug. By contrast, apoptosis mediated by caspase-3/-7 was not affected by NTS. Mice pretreated with NTS intraperitoneally displayed improved survival rate and extended survival time in LPS- and polymicrobe-induced septic models respectively. In conclusion, NTS is a selective inhibitor of inflammatory caspases which blocks both the non-canonical and canonical pyroptotic pathways. It is safe for intraperitoneal administration and might be used as a prototype to develop drugs for sepsis treatments.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Nitrosonisoldipine ⋅ Pyroptosis ⋅ Septic Shock ⋅ Caspases ⋅ Inflammation
ISSN (print) / ISBN 0014-2980
e-ISSN 1521-4141
Journal European Journal of Immunology
Quellenangaben Volume: 51, Issue: 5, Pages: 1234-1245 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
Grants Collaborative Innovation of Industry, University, and Research Institute Major Program of Guangzhou
Fundamental Research Funds for the Central Universities
Natural Science Foundation of Jiangsu Province
National Natural Science Foundation of China
Ministry of Science and Technology of China