1. TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice.
- Author
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Kökten T, Gibot S, Lepage P, D'Alessio S, Hablot J, Ndiaye NC, Busby-Venner H, Monot C, Garnier B, Moulin D, Jouzeau JY, Hansmannel F, Danese S, Guéant JL, Muller S, and Peyrin-Biroulet L
- Subjects
- Animals, Colitis chemically induced, DNA, Bacterial analysis, Dextran Sulfate, Disease Models, Animal, Dysbiosis prevention & control, Feces chemistry, Gastrointestinal Microbiome drug effects, Gastrointestinal Microbiome genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Triggering Receptor Expressed on Myeloid Cells-1 blood, Unfolded Protein Response drug effects, Unfolded Protein Response genetics, Autophagy drug effects, Autophagy genetics, Colitis drug therapy, Endoplasmic Reticulum Stress drug effects, Endoplasmic Reticulum Stress genetics, Peptides pharmacology, Triggering Receptor Expressed on Myeloid Cells-1 antagonists & inhibitors, Triggering Receptor Expressed on Myeloid Cells-1 genetics
- Abstract
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., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)
- Published
- 2018
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