FADD and Caspase-8 Mediate Priming and Activation of the Canonical and Noncanonical Nlrp3 Inflammasomes

Abstract

The Nlrp3 inflammasome is critical for host immunity, but the mechanisms controlling its activation are enigmatic. Here, we show that loss of FADD or caspase-8 in a RIP3-deficient background - but not RIP3-deficiency alone - hampered transcriptional priming and post-translational activation of the canonical and non-canonical Nlrp3 inflammasome. Deletion of caspase-8 in the presence or absence of RIP3 inhibited caspase-1 and caspase-11 activation by Nlrp3 stimuli, but not the Nlrc4 inflammasome. FADD deletion in addition prevented caspase-8 maturation, positioning FADD upstream of caspase-8. Consequently, FADD- and caspase-8-deficient mice had impaired IL-1β production when challenged with LPS or infected with the enteropathogen C. rodentium. Thus, our results reveal FADD and caspase-8 as apical mediators of canonical and non-canonical Nlrp3 inflammasome priming and activation.

Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma

“…Our findings demonstrated that inhibition of caspase-8 signaling decreased the activation of NLRP1, NLRP3, ASC, and caspase-1, implicating caspase-8 as an important link between TLR4 and inflammasomes and a mediator of IOP-induced RGC death. Gurung et al also observed that caspase-8 could regulate the activation of caspase-1 in cultured macrophages (35).…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…In contrast, deletion of caspase-8 or FADD in a RIP3-deficient background eliminates the caspase-1 activation and the production of mature IL-1b in response to LPS/ATP stimulation or C. rodentium infection, indicating positive regulation of inflammasome activation by caspase-8 (Gurung et al 2014). Caspase-8 was shown to be involved in the expression of inflammasome-related and pro-IL-1b genes and activation of the NLRP3 inflammasome (Gurung et al 2014). These results indicate that caspase-8 plays important roles in the positive and negative regulation of inflammatory responses mediated by the NLRP3 inflammasome.…”

“…In a basal condition, RIP3 contributes to the activation of the NLRP3 inflammasome, which is inhibited by caspase-8 under certain conditions (Kang et al 2013). In contrast, deletion of caspase-8 or FADD in a RIP3-deficient background eliminates the caspase-1 activation and the production of mature IL-1b in response to LPS/ATP stimulation or C. rodentium infection, indicating positive regulation of inflammasome activation by caspase-8 (Gurung et al 2014). Caspase-8 was shown to be involved in the expression of inflammasome-related and pro-IL-1b genes and activation of the NLRP3 inflammasome (Gurung et al 2014).…”

Inflammasome Priming in Sterile Inflammatory Disease

“…A second study showed that, similarly to NLRP3, complement might also prime caspase-11 activity, although via a separate mechanism in which complement-related peptidase Cbp1 (carboxypeptidase B1) cleaves C3 to trigger C3aR [128] . Fas-associated protein with death domain (FADD) and caspase-8 in TLR4-NF-κB have also been proposed to prime both canonical and non-canonical inflammasomes [129]. This is intriguing, given the profound caspase-8-driven gut pathology that is associated with necroptosis of intestinal epithelial cells, which might connect the necroptotic and pyroptotic pathways implicated in IBD and sepsis in association with Gramnegative bacteria [130] .…”