The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation

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


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.

MeSH terms

  • Animals
  • Chemokine CCL2 / metabolism
  • Chemokine CXCL1 / metabolism
  • Chemokine CXCL2 / metabolism
  • Colitis / chemically induced
  • Colitis / complications
  • Colitis / metabolism*
  • Colitis / 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*
  • Receptors, G-Protein-Coupled / metabolism*
  • Rectal Prolapse / etiology*
  • Rectal Prolapse / genetics
  • T-Lymphocytes, Helper-Inducer / pathology


  • 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