Universität zu Köln

Vlantis, Katerina, Polykratis, Apostolos ORCID: 0000-0001-6720-3302, Welz, Patrick-Simon ORCID: 0000-0001-8370-625X, van Loo, Geert, Pasparakis, Manolis ORCID: 0000-0002-9870-0966 and Wullaert, Andy ORCID: 0000-0001-5012-654X (2016). TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice. Gut, 65 (6). S. 935 - 944. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-3288

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Abstract

Objective The gut microbiota modulates host susceptibility to intestinal inflammation, but the cell types and the signalling pathways orchestrating this bacterial regulation of intestinal homeostasis remain poorly understood. Here, we investigated the function of intestinal epithelial toll-like receptor (TLR) responses in the dextran sodium sulfate (DSS)-induced mouse model of colitis. Design We applied an in vivo genetic approach allowing intestinal epithelial cell (IEC)-specific deletion of the critical TLR signalling adaptors, MyD88 and/or TIR-domain-containing adapter-inducing interferon-beta (TRIF), as well as the downstream ubiquitin ligase TRAF6 in order to reveal the IEC-intrinsic function of these TLR signalling molecules during DSS colitis. Results Mice lacking TRAF6 in IECs showed exacerbated DSS-induced inflammatory responses that ensued in the development of chronic colon inflammation. Antibiotic pretreatment abolished the increased DSS susceptibility of these mice, showing that epithelial TRAF6 signalling pathways prevent the gut microbiota from driving excessive colitis. However, in contrast to epithelial TRAF6 deletion, blocking epithelial TLR signalling by simultaneous deletion of MyD88 and TRIF specifically in IECs did not affect DSS-induced colitis severity. This in vivo functional comparison between TRAF6 and MyD88/TRIF deletion in IECs shows that the colitis-protecting effects of epithelial TRAF6 signalling are not triggered by TLRs. Conclusions Intestinal epithelial TRAF6-dependent but MyD88/TRIF-independent and, thus, TLR-independent signalling pathways are critical for preventing propagation of DSS-induced colon inflammation by the gut microbiota. Moreover, our experiments using mice with dual MyD88/TRIF deletion in IECs unequivocally show that the gut microbiota trigger non-epithelial TLRs rather than epithelial TLRs to restrict DSS colitis severity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Vlantis, Katerina UNSPECIFIED UNSPECIFIED UNSPECIFIED Polykratis, Apostolos UNSPECIFIED orcid.org/0000-0001-6720-3302 UNSPECIFIED Welz, Patrick-Simon UNSPECIFIED orcid.org/0000-0001-8370-625X UNSPECIFIED van Loo, Geert UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Wullaert, Andy UNSPECIFIED orcid.org/0000-0001-5012-654X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-275041
DOI:	10.1136/gutjnl-2014-308323
Journal or Publication Title:	Gut
Volume:	65
Number:	6
Page Range:	S. 935 - 944
Date:	2016
Publisher:	BMJ PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1468-3288
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TOLL-LIKE RECEPTOR-4; BARRIER FUNCTION; OPPOSING FUNCTIONS; MYELOID CELLS; MOUSE MODEL; IKK-BETA; IN-VIVO; INFLAMMATION; HOMEOSTASIS; INJURY Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27504