Article Text

Original article
TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice
  1. Katerina Vlantis1,2,3,
  2. Apostolos Polykratis1,2,3,
  3. Patrick-Simon Welz1,2,3,4,
  4. Geert van Loo5,6,
  5. Manolis Pasparakis1,2,3,
  6. Andy Wullaert1,2,3,7,8
  1. 1Institute for Genetics, University of Cologne, Cologne, Germany
  2. 2Centre for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
  3. 3Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
  4. 4Institute for Research in Biomedicine (IRB), Barcelona, Spain
  5. 5Inflammation Research Center, VIB, Ghent, Belgium
  6. 6Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
  7. 7Department of Medical Protein Research, VIB, Ghent, Belgium
  8. 8Department of Biochemistry, Ghent University, Ghent, Belgium
  1. Correspondence to Dr Andy Wullaert, Department of Medical Protein Research, VIB; Department of Biochemistry, Ghent University, Technologiepark 927, 9052 Ghent, Belgium; andy.wullaert{at}ugent.be Dr Manolis Pasparakis, CECAD Research Center, Institute for Genetics, University of Cologne, Joseph-Stelzmann-Str. 26, D50931 Cologne, Germany; pasparakis{at}uni-koeln.de

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-β (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.

  • EXPERIMENTAL COLITIS
  • GUT INFLAMMATION

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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