pH-Sensing G Protein-Coupled Receptor OGR1 (GPR68) Expression and Activation Increases in Intestinal Inflammation and Fibrosis |
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| Authors: | Cheryl de Valliè re,Jesus Cosin-Roger,Katharina Baebler,Anja Schoepflin,Cé line Mamie,Michelle Mollet,Cordelia Schuler,Susan Bengs,Silvia Lang,Michael Scharl,Klaus Seuwen,Pedro A. Ruiz,Martin Hausmann,Gerhard Rogler |
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| Affiliation: | 1.Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; (C.d.V.); (J.C.-R.); (K.B.); (C.M.); (M.M.); (C.S.); (S.B.); (S.L.); (M.S.); (P.A.R.); (M.H.);2.Sophistolab, 4132 Muttenz, Switzerland;3.Zurich Center for Integrative Human Physiology, 8057 Zurich, Switzerland;4.Novartis Institutes for Biomedical Research, 4033 Basel, Switzerland; |
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| 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. |
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| Keywords: | OGR1 (GPR68) expression and function pH-sensing GPCR inflammatory bowel disease fibrosis fibroblasts |
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