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The proton-activated receptor GPR4 modulates intestinal inflammation


Abstract

BACKGROUND AND AIMS: During active inflammation tissue intraluminal intestinal pH is decreased in patients with inflammatory bowel disease (IBD). Acidic pH may play a role in IBD pathophysiology. Recently, proton sensing G-protein coupled receptors were identified, including GPR4, OGR1 (GPR68), and TDAG8 (GPR65). We investigated whether GPR4 is involved in intestinal inflammation.
METHODS: The role of GPR4 was assessed in murine colitis models: chronic dextran sulphate sodium (DSS) administration and by crossbreeding into an IL-10 deficient background for development of spontaneous colitis. Colitis severity was assessed by body weight, colonoscopy, colon length, histological score, cytokine mRNA expression, and myeloperoxidase (MPO) activity. In the spontaneous Il-10-/- colitis model, the incidence of rectal prolapse and characteristics of lamina propria leukocytes (LPLs) were analyzed.
RESULTS: Gpr4-/- mice showed reduced body weight loss and histology score after induction of chronic DSS colitis. In Gpr4-/- /Il-10-/- double knock-outs the onset and progression of rectal prolapse were significantly delayed and mitigated compared to Gpr4+/+ /Il-10-/- mice. Double knock-out mice showed lower histology scores, MPO activity, CD4 + T-helper cell infiltration, IFN-γ, iNOS, MCP-1 (CCL2), CXCL1 and CXCL2 expression compared to controls. In colon, GPR4 mRNA was detected in endothelial cells, some smooth muscle cells, and some macrophages.
CONCLUSION: Absence of GPR4 ameliorates colitis in IBD animal models indicating an important regulatory rolein mucosal inflammation, thus providing a new link between tissue pH and the immune system. Therapeutic inhibition of GPR4 may be beneficial for the treatment of IBD.

Abstract

BACKGROUND AND AIMS: During active inflammation tissue intraluminal intestinal pH is decreased in patients with inflammatory bowel disease (IBD). Acidic pH may play a role in IBD pathophysiology. Recently, proton sensing G-protein coupled receptors were identified, including GPR4, OGR1 (GPR68), and TDAG8 (GPR65). We investigated whether GPR4 is involved in intestinal inflammation.
METHODS: The role of GPR4 was assessed in murine colitis models: chronic dextran sulphate sodium (DSS) administration and by crossbreeding into an IL-10 deficient background for development of spontaneous colitis. Colitis severity was assessed by body weight, colonoscopy, colon length, histological score, cytokine mRNA expression, and myeloperoxidase (MPO) activity. In the spontaneous Il-10-/- colitis model, the incidence of rectal prolapse and characteristics of lamina propria leukocytes (LPLs) were analyzed.
RESULTS: Gpr4-/- mice showed reduced body weight loss and histology score after induction of chronic DSS colitis. In Gpr4-/- /Il-10-/- double knock-outs the onset and progression of rectal prolapse were significantly delayed and mitigated compared to Gpr4+/+ /Il-10-/- mice. Double knock-out mice showed lower histology scores, MPO activity, CD4 + T-helper cell infiltration, IFN-γ, iNOS, MCP-1 (CCL2), CXCL1 and CXCL2 expression compared to controls. In colon, GPR4 mRNA was detected in endothelial cells, some smooth muscle cells, and some macrophages.
CONCLUSION: Absence of GPR4 ameliorates colitis in IBD animal models indicating an important regulatory rolein mucosal inflammation, thus providing a new link between tissue pH and the immune system. Therapeutic inhibition of GPR4 may be beneficial for the treatment of IBD.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Immunology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Gastroenterology
Language:English
Date:2018
Deposited On:10 Jan 2018 15:38
Last Modified:13 May 2020 22:02
Publisher:Oxford University Press
ISSN:1873-9946
Additional Information:This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Journal of Crohn's & Colitis following peer review. The definitive publisher-authenticated version Yu Wang, Cheryl de Vallière, Pedro H Imenez Silva, Irina Leonardi, Sven Gruber, Alexandra Gerstgrasser, Hassan Melhem, Achim Weber, Katharina Leucht, Lutz Wolfram, Martin Hausmann, Carsten Krieg, Koray Thomasson, Onur Boyman, Isabelle Frey-Wagner, Gerhard Rogler, Carsten A Wagner; The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation, Journal of Crohn's and Colitis, , jjx147 is available online at: doi.org/10.1093/ecco-jcc/jjx147.
OA Status:Green
Publisher DOI:https://doi.org/10.1093/ecco-jcc/jjx147
PubMed ID:29136128
Project Information:
  • : FunderFP7
  • : Grant ID608847
  • : Project TitleIKPP2 - International Fellowship Program on Integrative Kidney Physiology and Pathophysiology

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