PH-Sensing G Protein-Coupled Receptor OGR1 (GPR68) Expression and Activation Increases in Intestinal Inflammation and Fibrosis.

Cheryl De Vallière,Michelle Mollet,Katharina Baebler,Anja Schoepflin,Martin Hausmann,Silvia Lang,Céline Mamie,Gerhard Rogler,Jesus Cosin-Roger,Cordelia Schuler,Klaus Seuwen,Michael Scharl,Susan Bengs,Pedro A Ruiz

doi:10.3390/ijms23031419

Abstract

Local extracellular acidification occurs at sites of inflammation. Proton-sensing ovarian cancer G-protein-coupled receptor 1 (OGR1, also known as GPR68) responds to decreases in extracellular pH. Our previous studies show a role for OGR1 in the pathogenesis of mucosal inflammation, suggesting a link between tissue pH and immune responses. Additionally, pH-dependent signalling is associated with the progression of intestinal fibrosis. In this study, we aimed to investigate OGR1 expression and OGR1-mediated signalling in patients with inflammatory bowel disease (IBD). Our results show that OGR1 expression significantly increased in patients with IBD compared to non-IBD patients, as demonstrated by qPCR and immunohistochemistry (IHC). Paired samples from non-inflamed and inflamed intestinal areas of IBD patients showed stronger OGR1 IHC staining in inflamed mucosal segments compared to non-inflamed mucosa. IHC of human surgical samples revealed OGR1 expression in macrophages, granulocytes, endothelial cells, and fibroblasts. OGR1-dependent inositol phosphate (IP) production was significantly increased in CD14+ monocytes from IBD patients compared to healthy subjects. Primary human and murine fibroblasts exhibited OGR1-dependent IP formation, RhoA activation, F-actin, and stress fibre formation upon an acidic pH shift. OGR1 expression and signalling increases with IBD disease activity, suggesting an active role of OGR1 in the pathogenesis of IBD.

Highlights

The development of an acidic tissue environment is a hallmark feature of a variety of inflammatory processes
We found that OGR1 is strongly regulated by hypoxia and tumour necrosis factor (TNF) via the nuclear factor (NF)-κB signalling pathway and is essential for intestinal inflammation and fibrosis [23,24,25]
Our data show that OGR1 mRNA expression in inflamed colonic resections of Crohn’s disease (CD) and ulcerative colitis (UC) patients increased five-fold and ten-fold, respectively, compared to mucosal resections from non-inflammatory bowel disease (IBD) control subjects (Figure 1A), thereby confirming our previous results [23,24]

Summary

Introduction

The development of an acidic tissue environment is a hallmark feature of a variety of inflammatory processes. The association between extracellular tissue acidification and intestinal inflammation is ascribed to increased metabolic demand from infiltrating immune cells, which leads to enhanced glucose consumption and lactic acid formation [3,4,5,6]. Hypoxia, a common feature in intestinal inflammation, has been shown to decrease the local pH in the mucosal tissue [7]. During severe inflammation, reduced mucosal bicarbonate secretion, increased bacterial lactate production, and decreased short chain fatty acids might contribute to the low pH in an IBD patient’s colon [12,13]. OGR1 couples predominantly through Gq11 proteins, leading to activation of the phospholipase C (PLC)/inositol phosphate (IP)/Ca2+/extracellular signal-regulated kinases (ERK) pathway [14]. Our previous study suggests the involvement of the Gα12/13/Rho signalling pathway [18], which has been reported by others [19,20,21,22]

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