TREM-1 inhibition restores impaired autophagy activity and reduces colitis in mice

Tunay Kökten, Sébastien Gibot, Sébastien Gibot, Patricia Lepage, Silvia D'Alessio, Silvia D'Alessio, Julie Hablot, Ndeye Coumba Ndiaye, Hélène Busby-Venner, Céline Monot, Benjamin Garnier, David Moulin, Jean Yves Jouzeau, Franck Hansmannel, Silvio Danese, Silvio Danese, Jean Louis Guéant, Sylviane Muller, Laurent Peyrin-Birouleta, Laurent Peyrin-Birouleta

Research output: Contribution to journalArticlepeer-review


© 2017 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. Background and Aims: Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD] . Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy and ER stress and preventing dysbiosis. Methods: An experimental mouse model of colitis was established by dextran sulphate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knock-out [KO] mice. Colon tissues and faecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA] , and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals. Results: We confirmed that inhibition of TREM-1 attenuates the severity of colitis clinically, endoscopically and histologically. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1] , whereas there was a decrease in the UPR [PERK, IRE-1α, and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis. Conclusions: TREM-1 may represent a novel drug target for the treatment of IBD, by modulating autophagy activity and ER stress.
Original languageEnglish
Pages (from-to)230-244
Number of pages15
JournalJournal of Crohn's and Colitis
Issue number2
Publication statusPublished - Jan 24 2018


  • Animal models of IBD
  • Autophagy
  • Dysbiosis
  • Endoplasmic reticulum stress
  • Endoscopy
  • Inflammation
  • Inflammatory bowel disease
  • Innovative therapy
  • LR12 peptide
  • Peptide-based therapy
  • TREM-1


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