1. TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice.
- Author
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Kökten, Tunay, Gibot, Sébastien, Lepage, Patricia, D'Alessio, Silvia, Hablot, Julie, Ndiaye, Ndeye-Coumba, Busby-Venner, Hélène, Monot, Céline, Garnier, Benjamin, Moulin, David, Jouzeau, Jean-Yves, Hansmannel, Franck, Danese, Silvio, Guéant, Jean-Louis, Muller, Sylviane, and Peyrin-Biroulet, Laurent more...
- 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. [ABSTRACT FROM AUTHOR] more...
- Published
- 2018
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