期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 51, 期 5, 页码 1234-1245出版社
WILEY
DOI: 10.1002/eji.202048937
关键词
caspases; inflammation; nitrosonisoldipine; pyroptosis; septic shock
类别
资金
- Ministry of Science and Technology of China [2019YFC1711000, 2018YFA0801100]
- National Natural Science Foundation of China [31772550, 31971056]
- Natural Science Foundation of Jiangsu Province [BK20181260]
- Fundamental Research Funds for the Central Universities [14380034]
- Collaborative Innovation of Industry, University, and Research Institute Major Program of Guangzhou [201604046020]
The study identified nitrosonisoldipine (NTS) as a selective inhibitor of inflammatory caspases, blocking both noncanonical and canonical pyroptotic pathways, with potential therapeutic value for sepsis.
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 that nitrosonisoldipine (NTS), a photodegradation product of calcium channel inhibitor nisoldipine, inhibits noncanonical pyroptosis. Using murine immortalized BM-derived macrophage and human THP-1 cell line, we further discovered that NTS not only inhibits noncanonical 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 that blocks both the noncanonical 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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