Caspase-8 controls the gut response to microbial challenges by Tnf-alpha-dependent and independent pathways

Gunther, Claudia, Buchen, Barbara, He, Gui-Wei, Hornef, Mathias, Torow, Natalia, Neumann, Helmut, Wittkopf, Nadine, Martini, Eva, Basic, Marijana, Bleich, André, Watson, Alastair J. M. ORCID:, Neurath, Markus F. and Becker, Christoph (2015) Caspase-8 controls the gut response to microbial challenges by Tnf-alpha-dependent and independent pathways. Gut, 64 (4). pp. 601-610. ISSN 0017-5749

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Objectives: Intestinal epithelial cells (IEC) express toll-like receptors (TLR) that facilitate microbial recognition. Stimulation of TLR ligands induces a transient increase in epithelial cell shedding, a mechanism that serves the antibacterial and antiviral host defence of the epithelium and promotes elimination of intracellular pathogens. Although activation of the extrinsic apoptosis pathway has been described during inflammatory shedding, its functional involvement is currently unclear. Design: We investigated the functional involvement of caspase-8 signalling in microbial-induced intestinal cell shedding by injecting Lipopolysaccharide (LPS) to mimic bacterial pathogens and poly(I:C) as a probe for RNA viruses in vivo. Results: TLR stimulation of IEC was associated with a rapid activation of caspase-8 and increased epithelial cell shedding. In mice with an epithelial cell-specific deletion of caspase-8 TLR stimulation caused Rip3-dependent epithelial necroptosis instead of apoptosis. Mortality and tissue damage were more severe in mice in which IECs died by necroptosis than apoptosis. Inhibition of receptor-interacting protein (Rip) kinases rescued the epithelium from TLR-induced gut damage. TLR3-induced necroptosis was directly mediated via TRIF-dependent pathways, independent of Tnf-α and type III interferons, whereas TLR4-induced tissue damage was critically dependent on Tnf-α. Conclusions: Together, our data demonstrate an essential role for caspase-8 in maintaining the gut barrier in response to mucosal pathogens by permitting inflammatory shedding and preventing necroptosis of infected cells. These data suggest that therapeutic strategies targeting the cell death machinery represent a promising new option for the treatment of inflammatory and infective enteropathies.

Item Type: Article
Additional Information: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See:
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: Pure Connector
Date Deposited: 23 Sep 2014 14:18
Last Modified: 20 Aug 2023 13:30
DOI: 10.1136/gutjnl-2014-307226

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