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P017 OGR1 (GPR68) expression is increased in intestinal inflammation and correlates with disease activity in patients with IBD

Cosin-Roger J.1, Bengs S.1, Lang S.1, Turina M.2, Rickenbacher A.2, Seuwen K.3, Ruiz P.A.1, Misselwitz B.1, Rogler G.1, de Vallière C.*1

1University Hospital Zurich, University of Zurich, Gastroenterology and Hepatology, Zurich, Switzerland 2University Hospital Zurich, Clinic of Visceral and Transplantation Surgery, Zurich, Switzerland 3Novartis Institutes for Biomedical Research, Basel, Switzerland

Background

A family of pH-sensing G-protein coupled receptors (GPCRs), including ovarian cancer G-protein coupled receptor 1 (OGR1), T-cell death-associated gene 8 (TDAG8 or GPR65) and G-protein coupled receptor 4 (GPR4) play an important role in physiological pH homeostasis. Gut-wall inflammation in both forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), is associated with extracellular tissue acidification. Recent studies reported a link between IBD and this family of pH-sensing receptors. TDAG8 has been identified as an IBD-risk gene. We previously reported that OGR1 is strongly regulated by TNF via a NF-κB dependent pathway and is essential for intestinal inflammation and fibrosis. We showed that genetic ablation of OGR1 and GPR4 ameliorates colitis in different murine models. Further, we demonstrated that OGR1 regulates barrier function and epithelial restoration, and that OGR1 expression is enhanced by hypoxia.

Methods

Expression of OGR1 in surgical specimens from non-IBD (n=5), CD (n=10) and UC (n=10) patients was determined by immunohistochemistry, RT-qPCR and Western blotting. Clinical disease activity was assessed by the Harvey Bradshaw Index and the Modified Truelove and Witts activity index (MTWAI) for CD and UC patients, respectively. Nonparametric Spearman's rank correlation analysis was performed.

Results

OGR1 immunostaining of human surgical samples from non-IBD patients revealed OGR1 expression mainly in lamina propria cells, with weaker staining in epithelial cells. OGR1 staining in IBD patients was stronger compared to controls; however, in IBD patients OGR1 is highly expressed in both epithelial cells and cells in the lamina propria. Further, paired samples taken at the same time, from non-inflamed and inflamed intestinal tissue from IBD patients showed stronger OGR1 staining in the inflamed mucosa compared to the non-inflamed mucosa. Accordingly, mRNA and protein expression of OGR1 was significantly increased in patients with IBD compared to non-IBD patients. Additionally, a significant positive correlation was observed between OGR1 expression and the clinical score in both the non-inflamed (rs 0.7311, p=0.0069) and the inflamed mucosa (rs 0.7698, p=0.0034).

Conclusion

The expression of OGR1 is significantly increased in patients with IBD. OGR1 expression correlates with IBD disease activity, suggesting an active role of OGR1 in IBD pathogenesis.