Caspase-1 Engagement and TLR-Induced c-FLIP Expression Suppress ASC/Caspase-8-Dependent Apoptosis by Inflammasome Sensors NLRP1b and NLRC4

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Abstract

The caspase activation and recruitment domain (CARD)-based inflammasome sensors NLRP1b and NLRC4 induce caspase-1-dependent pyroptosis independent of the inflammasome adaptor ASC. Here, we show that NLRP1b and NLRC4 trigger caspase-8-mediated apoptosis as an alternative cell death program in caspase-1−/− macrophages and intestinal epithelial organoids (IECs). The caspase-8 adaptor FADD was recruited to ASC specks, which served as cytosolic platforms for caspase-8 activation and NLRP1b/NLRC4-induced apoptosis. We further found that caspase-1 protease activity dominated over scaffolding functions in suppressing caspase-8 activation and induction of apoptosis of macrophages and IECs. Moreover, TLR-induced c-FLIP expression inhibited caspase-8-mediated apoptosis downstream of ASC speck assembly, but did not affect pyroptosis induction by NLRP1b and NLRC4. Moreover, unlike during pyroptosis, NLRP1b- and NLRC4-elicited apoptosis retained alarmins and the inflammasome-matured cytokines interleukin 1β (IL-1β) and IL-18 intracellularly. This work identifies critical mechanisms regulating apoptosis induction by the inflammasome sensors NLRP1b and NLRC4 and suggests converting pyroptosis into apoptosis as a paradigm for suppressing inflammation. Van Opdenbosch et al. find that CARD-based inflammasome sensors drive ASC- and caspase-8-dependent apoptosis as an alternative cell death program when caspase-1 activation is impaired. TLR-mediated upregulation of c-FLIP is identified as a second checkpoint that regulates ASC/caspase-8-mediated apoptosis. Moreover, apoptosis differs from pyroptosis in retaining inflammasome-dependent cytokines and alarmins intracellularly.

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Van Opdenbosch, N., Van Gorp, H., Verdonckt, M., Saavedra, P. H. V., de Vasconcelos, N. M., Gonçalves, A., … Lamkanfi, M. (2017). Caspase-1 Engagement and TLR-Induced c-FLIP Expression Suppress ASC/Caspase-8-Dependent Apoptosis by Inflammasome Sensors NLRP1b and NLRC4. Cell Reports, 21(12), 3427–3444. https://doi.org/10.1016/j.celrep.2017.11.088

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