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

Publication date: 19 December 2017
Source:Cell Reports, Volume 21, Issue 12
Author(s): Nina Van Opdenbosch, Hanne Van Gorp, Maarten Verdonckt, Pedro H.V. Saavedra, Nathalia M. de Vasconcelos, Amanda Gonçalves, Lieselotte Vande Walle, Dieter Demon, Magdalena Matusiak, Filip Van Hauwermeiren, Jinke D'Hont, Tino Hochepied, Stefan Krautwald, Thirumala-Devi Kanneganti, Mohamed Lamkanfi
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.

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Teaser

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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