TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice
Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissionsoup.com.
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Journal of Crohn's & colitis - 12(2018), 2 vom: 24. Jan., Seite 230-244 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kökten, Tunay [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.09.2018 Date Revised 16.03.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/ecco-jcc/jjx129 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM276316452 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissionsoup.com | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: TREM-1 may represent a novel drug target for the treatment of IBD, by modulating autophagy activity and ER stress | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Animal models of IBD | |
| 650 | 4 | |a LR12 peptide | |
| 650 | 4 | |a TREM-1 | |
| 650 | 4 | |a autophagy | |
| 650 | 4 | |a dysbiosis | |
| 650 | 4 | |a endoplasmic reticulum stress | |
| 650 | 4 | |a endoscopy | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a inflammatory bowel disease | |
| 650 | 4 | |a innovative therapy | |
| 650 | 4 | |a peptide-based therapy | |
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| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a TREM1 protein, mouse |2 NLM | |
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| 650 | 7 | |a 9042-14-2 |2 NLM | |
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| 700 | 1 | |a Lepage, Patricia |e verfasserin |4 aut | |
| 700 | 1 | |a D'Alessio, Silvia |e verfasserin |4 aut | |
| 700 | 1 | |a Hablot, Julie |e verfasserin |4 aut | |
| 700 | 1 | |a Ndiaye, Ndeye-Coumba |e verfasserin |4 aut | |
| 700 | 1 | |a Busby-Venner, Hélène |e verfasserin |4 aut | |
| 700 | 1 | |a Monot, Céline |e verfasserin |4 aut | |
| 700 | 1 | |a Garnier, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Moulin, David |e verfasserin |4 aut | |
| 700 | 1 | |a Jouzeau, Jean-Yves |e verfasserin |4 aut | |
| 700 | 1 | |a Hansmannel, Franck |e verfasserin |4 aut | |
| 700 | 1 | |a Danese, Silvio |e verfasserin |4 aut | |
| 700 | 1 | |a Guéant, Jean-Louis |e verfasserin |4 aut | |
| 700 | 1 | |a Muller, Sylviane |e verfasserin |4 aut | |
| 700 | 1 | |a Peyrin-Biroulet, Laurent |e verfasserin |4 aut | |
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