Format

Send to

Choose Destination
J Crohns Colitis. 2018 Feb 28;12(3):355-368. doi: 10.1093/ecco-jcc/jjx147.

The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation.

Author information

1
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
2
Institute of Physiology, University of Zurich, Zurich, Switzerland.
3
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
4
Laboratory of Applied Immunobiology, University of Zurich, Zurich, Switzerland.
5
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
6
Department of Immunology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

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.

PMID:
29136128
DOI:
10.1093/ecco-jcc/jjx147
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for Zurich Open Access Repository and Archive
Loading ...
Support Center