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.
Wang, Yu