TY - JOUR
T1 - Intestinal Activation of pH-Sensing Receptor OGR1 [GPR68] Contributes to Fibrogenesis
AU - Hutter, Senta
AU - Van Haaften, Wouter T.
AU - Hünerwadel, Anouk
AU - Baebler, Katharina
AU - Herfarth, Neel
AU - Raselli, Tina
AU - Mamie, Céline
AU - Misselwitz, Benjamin
AU - Rogler, Gerhard
AU - Weder, Bruce
AU - Dijkstra, Gerard
AU - Meier, Chantal Florence
AU - De Vallière, Cheryl
AU - Weber, Achim
AU - Imenez Silva, Pedro H.
AU - Wagner, Carsten A.
AU - Frey-Wagner, Isabelle
AU - Ruiz, Pedro A.
AU - Hausmann, Martin
N1 - Publisher Copyright:
Copyright © 2018 European Crohn's and Colitis Organisation (ECCO).
PY - 2018/11
Y1 - 2018/11
N2 - Background and Aims: pH-sensing ovarian cancer G-protein coupled receptor-1 [OGR1/GPR68] is regulated by key inflammatory cytokines. Patients suffering from inflammatory bowel diseases [IBDs] express increased mucosal levels of OGR1 compared with non-IBD controls. pH-sensing may be relevant for progression of fibrosis, as extracellular acidification leads to fibroblast activation and extracellular matrix remodelling. We aimed to determine OGR1 expression in fibrotic lesions in the intestine of Crohn's disease [CD] patients, and the effect of Ogr1 deficiency in fibrogenesis. Methods: Human fibrotic and non-fibrotic terminal ileum was obtained from CD patients undergoing ileocaecal resection due to stenosis. Gene expression of fibrosis markers and pH-sensing receptors was analysed. For the initiation of fibrosis in vivo, spontaneous colitis by Il10-/-, dextran sodium sulfate [DSS]-induced chronic colitis and the heterotopic intestinal transplantation model were used. Results: Increased expression of fibrosis markers was accompanied by an increase in OGR1 [2.71 ± 0.69 vs 1.18 ± 0.03, p = 0.016] in fibrosis-affected human terminal ileum, compared with the non-fibrotic resection margin. Positive correlation between OGR1 expression and pro-fibrotic cytokines [TGFB1 and CTGF] and pro-collagens was observed. The heterotopic animal model for intestinal fibrosis transplanted with terminal ileum from Ogr1-/- mice showed a decrease in mRNA expression of fibrosis markers as well as a decrease in collagen layer thickness and hydroxyproline compared with grafts from wild-type mice. Conclusions: OGR1 expression was correlated with increased expression levels of pro-fibrotic genes and collagen deposition. Ogr1 deficiency was associated with a decrease in fibrosis formation. Targeting OGR1 may be a potential new treatment option for IBD-associated fibrosis.
AB - Background and Aims: pH-sensing ovarian cancer G-protein coupled receptor-1 [OGR1/GPR68] is regulated by key inflammatory cytokines. Patients suffering from inflammatory bowel diseases [IBDs] express increased mucosal levels of OGR1 compared with non-IBD controls. pH-sensing may be relevant for progression of fibrosis, as extracellular acidification leads to fibroblast activation and extracellular matrix remodelling. We aimed to determine OGR1 expression in fibrotic lesions in the intestine of Crohn's disease [CD] patients, and the effect of Ogr1 deficiency in fibrogenesis. Methods: Human fibrotic and non-fibrotic terminal ileum was obtained from CD patients undergoing ileocaecal resection due to stenosis. Gene expression of fibrosis markers and pH-sensing receptors was analysed. For the initiation of fibrosis in vivo, spontaneous colitis by Il10-/-, dextran sodium sulfate [DSS]-induced chronic colitis and the heterotopic intestinal transplantation model were used. Results: Increased expression of fibrosis markers was accompanied by an increase in OGR1 [2.71 ± 0.69 vs 1.18 ± 0.03, p = 0.016] in fibrosis-affected human terminal ileum, compared with the non-fibrotic resection margin. Positive correlation between OGR1 expression and pro-fibrotic cytokines [TGFB1 and CTGF] and pro-collagens was observed. The heterotopic animal model for intestinal fibrosis transplanted with terminal ileum from Ogr1-/- mice showed a decrease in mRNA expression of fibrosis markers as well as a decrease in collagen layer thickness and hydroxyproline compared with grafts from wild-type mice. Conclusions: OGR1 expression was correlated with increased expression levels of pro-fibrotic genes and collagen deposition. Ogr1 deficiency was associated with a decrease in fibrosis formation. Targeting OGR1 may be a potential new treatment option for IBD-associated fibrosis.
UR - http://www.scopus.com/inward/record.url?scp=85056610408&partnerID=8YFLogxK
U2 - 10.1093/ecco-jcc/jjy118
DO - 10.1093/ecco-jcc/jjy118
M3 - Article
C2 - 30165600
AN - SCOPUS:85056610408
SN - 1873-9946
VL - 12
SP - 1348
EP - 1358
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
IS - 11
ER -
