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

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 N ，Van Gorp H ，Verdonckt M ，Saavedra PHV ，de Vasconcelos NM ，Gonçalves A ，Vande Walle L ，Demon D ，Matusiak M ，Van Hauwermeiren F ，D'Hont J ，Hochepied T ，Krautwald S ，Kanneganti TD ，Lamkanfi M ... -  《Cell Reports》

Caspase-1 autoproteolysis is differentially required for NLRP1b and NLRP3 inflammasome function.

Guey B ，Bodnar M ，Manié SN ，Tardivel A ，Petrilli V ... -  《-》

Cytokine Secretion and Pyroptosis of Thyroid Follicular Cells Mediated by Enhanced NLRP3, NLRP1, NLRC4, and AIM2 Inflammasomes Are Associated With Autoimmune Thyroiditis.

Guo Q ，Wu Y ，Hou Y ，Liu Y ，Liu T ，Zhang H ，Fan C ，Guan H ，Li Y ，Shan Z ，Teng W ... -  《Frontiers in Immunology》

Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation.

Van Opdenbosch N ，Gurung P ，Vande Walle L ，Fossoul A ，Kanneganti TD ，Lamkanfi M ... -  《Nature Communications》

DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages.

Activating germline mutations in the human inflammasome sensor NLRP1 causes palmoplantar dyskeratosis and susceptibility to Mendelian autoinflammatory diseases. Recent studies have shown that the cytosolic serine dipeptidyl peptidases DPP8 and DPP9 suppress inflammasome activation upstream of NLRP1 and CARD8 in human keratinocytes and peripheral blood mononuclear cells. Moreover, pharmacological inhibition of DPP8/DPP9 protease activity was shown to induce pyroptosis in murine C57BL/6 macrophages without eliciting other inflammasome hallmark responses. Here, we show that DPP8/DPP9 inhibition in macrophages that express a Bacillus anthracis lethal toxin (LeTx)-sensitive Nlrp1b allele triggered significantly accelerated pyroptosis concomitant with caspase-1 maturation, ASC speck assembly, and secretion of mature IL-1β and IL-18. Genetic ablation of ASC prevented DPP8/DPP9 inhibition-induced caspase-1 maturation and partially hampered pyroptosis and inflammasome-dependent cytokine release, whereas deletion of caspase-1 or gasdermin D triggered apoptosis in the absence of IL-1β and IL-18 secretion. In conclusion, blockade of DPP8/DPP9 protease activity triggers rapid pyroptosis and canonical inflammasome hallmarks in primary macrophages that express a LeTx-responsive Nlrp1b allele.

de Vasconcelos NM ，Vliegen G ，Gonçalves A ，De Hert E ，Martín-Pérez R ，Van Opdenbosch N ，Jallapally A ，Geiss-Friedlander R ，Lambeir AM ，Augustyns K ，Van Der Veken P ，De Meester I ，Lamkanfi M ... -  《Life Science Alliance》