G Protein-coupled pH-sensing Receptor OGR1 Is a Regulator of Intestinal Inflammation

The mechanisms involved in the maintenance of mucosal homeostasis are important in our understanding of the pathophysiology of inflammatory bowel disease (IBD). Both forms of the disease, Crohn's disease (CD) and ulcerative colitis (UC), give rise to inflammation that is associated with extracellular acidification of mucosal tissue. Mucosal inflammation is interpreted as a local response to tissue damage and microbial invasion. A number of studies suggest that an acidic environment affects the progression and resolution of inflammation.1–3 Inflammation has been attributed to an increase in local proton concentration and lactate production4 and subsequent proinflammatory cytokine production, such as tumur necrosis factor (TNF), interleukin-6 (IL-6), interferon gamma (IFN-γ), and interleukin-1-beta (IL-1β). TNF is one of the characterizing cytokines in IBD,5,6 and anti-TNF targeted therapies are successful in both CD and UC.7–10 Activated macrophages, which are key cellular mediators of acute and chronic inflammation, are primary producers of TNF.11 TNF activates the nuclear transcription factor kappa B (NF-κB), one of the key regulators in chronic mucosal inflammation.12,13 G protein-coupled receptors (GPCRs), cell-surface molecules involved in signal transduction, are targeted by key inflammatory cytokines.14 The ovarian cancer G protein-coupled receptor 1 (OGR1) family of receptors, which include OGR1, G protein-coupled receptor 4 (GPR4), and T-cell death associated gene (TDAG8), sense extracellular protons through histidine residues located on the extracellular region of the receptors, resulting in the modification of a variety of cell functions.15,16 Early signaling pathways of pH-sensing receptors triggered by acidification include phospholipase C activation, inositol trisphosphate formation, and subsequent Ca2+ release15 or cyclic adenosine monophosphate production.17,18 The increase of intracellular calcium influx and accumulation of cyclic adenosine monophosphate has been shown to regulate a vast range of cellular responses. Moreover, OGR1 and TDAG8 are alleged to act in opposition in a regulatory manner, either enhancing or inhibiting the production of proinflammatory cytokines respectively.19 TDAG8-mediated extracellular acidification inhibited lipopolysaccharide (LPS)-induced production of TNF and IL-6 in mouse peritoneal inflammatory macrophages.2 Patients with CD demonstrate a defect in macrophage function resulting in an inadequate bacterial clearance from inflammatory sites.20 In addition, macrophages from patients with CD showed impaired TNF-α secretion in response to bacterial challenge.21 Furthermore, association results and in silico analysis have recently identified a locus within the TDAG8 gene as one of the susceptibility loci associated with CD.22 Onozawa et al23 suggest that TDAG8 is a negative regulator of inflammation, which is mediated through a Gs-coupled mechanism.2 In contrast, OGR1 is reported to act predominately through a Gq-coupled mechanism to stimulate proinflammatory cytokines production upon extracellular acidification.19 To date, few data on the role of OGR1 in inflammation in IBD have been published. OGR1 may play an important role in the regulation of the inflammatory pathways in IBD, and it may represent an interesting target for innovative therapies. Therefore, we investigated the role and function of OGR1 in gut inflammation with a focus on myeloid cells. We used an immune-mediated inflammatory disease mouse model, namely interleukin-10 (Il-10) knockout (KO) mice, which spontaneously develop chronic colitis24–26 and a human monocyte model. We show that OGR1 expression is induced in monocytes by TNF and OGR1 deficiency protects from spontaneous inflammation in the Il-10 KO model.