The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation.

Abstract

BACKGROUND AND AIMS:

During active inflammation, 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 by chronic dextran sulphate sodium [DSS] administration and by cross-breeding 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 analysed.

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 with 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 with controls. In colon, GPR4 mRNA was detected in endothelial cells, some smooth muscle cells, and some macrophages.

CONCLUSIONS:

Absence of GPR4 ameliorates colitis in IBD animal models, indicating an important regulatory role in 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.

• Authors: 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
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 12 Issue 3 Pg. 355-368 (Feb 28 2018) ISSN: 1876-4479 [Electronic] England
• PMID: 29136128 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Chemokine CXCL1
• Chemokine CXCL2
• Cxcl1 protein, mouse
• Cxcl2 protein, mouse
• GPR4 protein, mouse
• Protons
• RNA, Messenger
• Receptors, G-Protein-Coupled
• Interleukin-10
• Interferon-gamma
• Dextran Sulfate
• Peroxidase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Chemokine CCL2 (metabolism)
• Chemokine CXCL1 (metabolism)
• Chemokine CXCL2 (metabolism)
• Colitis (chemically induced, complications, metabolism, pathology)
• Dextran Sulfate
• Endothelial Cells (metabolism)
• Female
• Hydrogen-Ion Concentration
• Interferon-gamma (metabolism)
• Interleukin-10 (genetics)
• Intestinal Mucosa (pathology)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Knockout
• Myocytes, Smooth Muscle (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Peroxidase (metabolism)
• Protons
• RNA, Messenger (metabolism)
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Rectal Prolapse (etiology, genetics)
• T-Lymphocytes, Helper-Inducer (pathology)