1. pH-Sensing G Protein-Coupled Receptor OGR1 (GPR68) Expression and Activation Increases in Intestinal Inflammation and Fibrosis
- Author
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de Vallière, Cheryl; https://orcid.org/0000-0002-8519-4451, Cosin-Roger, Jesus, Baebler, Katharina, Schoepflin, Anja, Mamie, Céline; https://orcid.org/0000-0003-1415-6674, Mollet, Michelle, Schuler, Cordelia, Bengs, Susan, Lang, Silvia; https://orcid.org/0000-0002-1216-899X, Scharl, Michael, Seuwen, Klaus, Ruiz, Pedro A, Hausmann, Martin, Rogler, Gerhard; https://orcid.org/0000-0002-1733-9188, de Vallière, Cheryl; https://orcid.org/0000-0002-8519-4451, Cosin-Roger, Jesus, Baebler, Katharina, Schoepflin, Anja, Mamie, Céline; https://orcid.org/0000-0003-1415-6674, Mollet, Michelle, Schuler, Cordelia, Bengs, Susan, Lang, Silvia; https://orcid.org/0000-0002-1216-899X, Scharl, Michael, Seuwen, Klaus, Ruiz, Pedro A, Hausmann, Martin, and Rogler, Gerhard; https://orcid.org/0000-0002-1733-9188
- 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. Keywords: OGR1 (GPR68) expression and function; fibroblasts; fibrosis; inflammatory bowel disease; pH-sensing GPCR.
- Published
- 2022