FADD and Caspase-8 Regulate Gut Homeostasis and Inflammation by Controlling MLKL- and GSDMD-Mediated Death of Intestinal Epithelial Cells

Abstract

Pathways controlling intestinal epithelial cell (IEC) death regulate gut immune homeostasis and contribute to the pathogenesis of inflammatory bowel diseases. Here, we show that caspase-8 and its adapter FADD act in IECs to regulate intestinal inflammation downstream of Z-DNA binding protein 1 (ZBP1)-and tumor necrosis factor receptor-1 (TNFR1)-mediated receptor interacting protein kinase 1 (RIPK1) and RIPK3 signaling. Mice with IEC-specific FADD or caspase-8 deficiency developed colitis dependent on mixed lineage kinase-like (MLKL)-mediated epithelial cell necroptosis. However, MLKL deficiency fully prevented ileitis caused by epithelial caspase-8 ablation, but only partially ameliorated ileitis in mice lacking FADD in IECs. Our genetic studies revealed that caspase-8 and gasdermin-D (GSDMD) were both required for the development of MLKL-independent ileitis in mice with epithelial FADD deficiency. Therefore, FADD prevents intestinal inflammation downstream of ZBP1 and TNFR1 by inhibiting both MLKL-induced necroptosis and caspase-8-GSDMD-dependent pyroptosis-like death of epithelial cells.

SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

“…Caspase-8 is a master regulator of several cell death pathways, including apoptosis, necroptosis, and pyroptosis. 19 Its role in regulation of inflammatory responses has been recently reported in the context of fungal infection. We found that SARS-CoV-2 induces caspase-8 activation to trigger cell apoptosis and to directly process inflammatory factors such as pro-IL-1β.…”

Pyroptotic cell death in the R6/2 mouse model of Huntington’s disease: new insight on the inflammasome

“…Recent studies have shown that pathways of cell death are associated in different ways according to the activation of signaling cascades inducing apoptosis, necroptosis, and pyroptosis 24 . An increasing body of evidence suggests that receptor interacting protein kinase 1 and caspase-8 are the mediators of the cross-talk between apoptosis, necroptosis, and pyroptosis and determine the type of cell death induced in response to activation of cell death signaling 25 .…”

“…The comparative study of the distribution of selected pyroptosis and apoptosis markers in the striatum showed that young mice, both wild type and R6/2, express high levels of the cleavage product of Caspase-8. We associate this phenomenon to the physiological process of cell homeostasis 25 , 27 . This was also confirmed by the lack of immunoreactivity for cleaved Caspase-8 in the 13-week-old mice, both wild type and R6/2.…”

Evolutionary loss of inflammasomes in carnivores to facilitate carriage of zoonotic infections

“…Inflammasome-driven lytic cell death is, therefore, lost in Canidae and this is particularly interesting because the Carnivora also lack the necroptotic effector MLKL such that two of the critical inflammatory cell death pathways that are thought to be essential for host protection against infection are absent. One of the key functions for inflammatory cell death is to protect the gut against infection (Crowley et al, 2020; Rauch et al, 2017; Schwarzer et al, 2020; Sellin et al, 2014; Tummers et al, 2020) yet canonical inflammasome, non-canonical inflammasome and necroptotic lytic cell death pathways in Carnivora are inactive. Emerging ecological evidence suggests that a high protein diet, such as that consumed by the Carnivora, is antimicrobial (Cotter et al, 2019) and we speculate that the evolutionary and functional reduction in inflammasome activation in the Carnivora may simply reflect the protection against infection conferred on these animals by their dietary habits.…”