PuSH - Publikationsserver des Helmholtz Zentrums München: Nitrosonisoldipine is a selective inhibitor of inflammatory caspases and protects against pyroptosis and related septic shock.

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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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