Immunity
Volume 52, Issue 6, 16 June 2020, Pages 978-993.e6
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Article
FADD and Caspase-8 Regulate Gut Homeostasis and Inflammation by Controlling MLKL- and GSDMD-Mediated Death of Intestinal Epithelial Cells

https://doi.org/10.1016/j.immuni.2020.04.002Get rights and content
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Highlights

  • TNFR1 and ZBP1 drive epithelial cell death and inflammation in the absence of FADD

  • MLK deficiency prevents both colitis and ileitis in mice lacking caspase-8 in IECs

  • MLKL causes colitis but partly contributes to ileitis in mice lacking FADD in IECs

  • Caspase-8 and GSDMD drive MLKL-independent ileitis in the absence of FADD

Summary

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.

Keywords

inflammatory bowel disease
cell death
apoptosis
necroptosis
pyroptosis
inflammation
FADD
Caspase-8
GSDMD
ZBP1

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