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 journalArticle

15 Citations (Scopus)

Abstract

© 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
Volume12
Issue number2
DOIs
Publication statusPublished - Jan 24 2018

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Autophagy
Myeloid Cells
Colitis
Unfolded Protein Response
Dysbiosis
Endoplasmic Reticulum Stress
Inflammatory Bowel Diseases
Inflammation
Dextran Sulfate
Microbiota
Knockout Mice
Colon
Proteins
Theoretical Models
Western Blotting
Peptides
Pharmaceutical Preparations

Keywords

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

Cite this

TREM-1 inhibition restores impaired autophagy activity and reduces colitis in mice. / Kökten, Tunay; Gibot, Sébastien; Gibot, Sébastien; Lepage, Patricia; D'Alessio, Silvia; D'Alessio, Silvia; Hablot, Julie; Ndiaye, Ndeye Coumba; Busby-Venner, Hélène; Monot, Céline; Garnier, Benjamin; Moulin, David; Jouzeau, Jean Yves; Hansmannel, Franck; Danese, Silvio; Danese, Silvio; Guéant, Jean Louis; Muller, Sylviane; Peyrin-Birouleta, Laurent; Peyrin-Birouleta, Laurent.

In: Journal of Crohn's and Colitis, Vol. 12, No. 2, 24.01.2018, p. 230-244.

Research output: Contribution to journalArticle

Kökten, T, Gibot, S, Gibot, S, Lepage, P, D'Alessio, S, D'Alessio, S, Hablot, J, Ndiaye, NC, Busby-Venner, H, Monot, C, Garnier, B, Moulin, D, Jouzeau, JY, Hansmannel, F, Danese, S, Danese, S, Guéant, JL, Muller, S, Peyrin-Birouleta, L & Peyrin-Birouleta, L 2018, 'TREM-1 inhibition restores impaired autophagy activity and reduces colitis in mice', Journal of Crohn's and Colitis, vol. 12, no. 2, pp. 230-244. https://doi.org/10.1093/ecco-jcc/jjx129
Kökten, Tunay ; Gibot, Sébastien ; Gibot, Sébastien ; Lepage, Patricia ; D'Alessio, Silvia ; D'Alessio, Silvia ; Hablot, Julie ; Ndiaye, Ndeye Coumba ; Busby-Venner, Hélène ; Monot, Céline ; Garnier, Benjamin ; Moulin, David ; Jouzeau, Jean Yves ; Hansmannel, Franck ; Danese, Silvio ; Danese, Silvio ; Guéant, Jean Louis ; Muller, Sylviane ; Peyrin-Birouleta, Laurent ; Peyrin-Birouleta, Laurent. / TREM-1 inhibition restores impaired autophagy activity and reduces colitis in mice. In: Journal of Crohn's and Colitis. 2018 ; Vol. 12, No. 2. pp. 230-244.
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AU - Kökten, Tunay

AU - Gibot, Sébastien

AU - Gibot, Sébastien

AU - Lepage, Patricia

AU - D'Alessio, Silvia

AU - D'Alessio, Silvia

AU - Hablot, Julie

AU - Ndiaye, Ndeye Coumba

AU - Busby-Venner, Hélène

AU - Monot, Céline

AU - Garnier, Benjamin

AU - Moulin, David

AU - Jouzeau, Jean Yves

AU - Hansmannel, Franck

AU - Danese, Silvio

AU - Danese, Silvio

AU - Guéant, Jean Louis

AU - Muller, Sylviane

AU - Peyrin-Birouleta, Laurent

AU - Peyrin-Birouleta, Laurent

PY - 2018/1/24

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N2 - © 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.

AB - © 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.

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