Schwarzer, Robin, Jiao, Huipeng, Wachsmuth, Laurens, Tresch, Achim and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2020). FADD and Caspase-8 Regulate Gut Homeostasis and Inflammation by Controlling MLKL- and GSDMD-Mediated Death of Intestinal Epithelial Cells. Immunity, 52.

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schwarzer, RobinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jiao, HuipengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wachsmuth, LaurensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tresch, AchimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis, Manolispasparakis@uni-koeln.deorcid.org/0000-0002-9870-0966UNSPECIFIED
URN: urn:nbn:de:hbz:38-111515
DOI: 10.1016/j.immuni.2020.04.002
Journal or Publication Title: Immunity
Volume: 52
Date: 16 June 2020
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: Life sciences
Related URLs:
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/11151

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