pH receptors; Crohn’s disease; innate immunity; G-protein coupled receptors; barrier function; mucosal immune system
Tcymbarevich Irina, Richards Shola M, Russo Giancarlo, Kühn-Georgijevic Jelena, Cosin-Roger Jesus, Baebler Katharina, Lang Silvia, Bengs Susan, Atrott Kirstin, Bettoni Carla, Gruber Sven, Frey-Wagner Isabelle, Scharl Michael, Misselwitz Benjamin, Wagner Carsten A, Seuwen Klaus, Rogler Gerhard, Ruiz Pedro A, Spalinger Marianne, de Vallière Cheryl (2019), Lack of the pH-sensing Receptor TDAG8 [GPR65] in Macrophages Plays a Detrimental Role in Murine Models of Inflammatory Bowel Disease, in Journal of Crohn's and Colitis
, 13(2), 245-258.
Tcymbarevich Irina (2019), The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation., in BMC Gastroenterol
, 19, 2.
Hutter Senta, van Haaften Wouter T, Hünerwadel Anouk, Baebler Katharina, Herfarth Neel, Raselli Tina, Mamie Céline, Misselwitz Benjamin, Rogler Gerhard, Weder Bruce, Dijkstra Gerard, Meier Chantal Florence, de Vallière Cheryl, Weber Achim, Imenez Silva Pedro H, Wagner Carsten A, Frey-Wagner Isabelle, Ruiz Pedro A, Hausmann Martin (2018), Intestinal Activation of pH-Sensing Receptor OGR1 [GPR68] Contributes to Fibrogenesis, in Journal of Crohn's and Colitis
, 15, 1348-1358.
Wang Yu, de Vallière Cheryl, Imenez Silva Pedro H, Leonardi Irina, Gruber Sven, Gerstgrasser Alexandra, Melhem Hassan, Weber Achim, Leucht Katharina, Wolfram Lutz, Hausmann Martin, Krieg Carsten, Thomasson Koray, Boyman Onur, Frey-Wagner Isabelle, Rogler Gerhard, Wagner Carsten A (2018), The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation, in Journal of Crohn's and Colitis
, 12(3), 355-368.
Cosin-Roger Jesus, Simmen Simona, Melhem Hassan, Atrott Kirstin, Frey-Wagner Isabelle, Hausmann Martin, de Vallière Cheryl, Spalinger Marianne R., Spielmann Patrick, Wenger Roland H., Zeitz Jonas, Vavricka Stephan R., Rogler Gerhard, Ruiz Pedro A. (2017), Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation, in Nature Communications
, 8(1), 98-98.
In uninflamed tissue, pH is normally maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. In both forms of inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), the gut-wall inflammation is associated with extracellular tissue acidification, which affects both, progression and resolution of inflammation. Low extracellular pH activates specific sensory pathways, in particular proteins of the G protein-coupled receptor (GPCR) family. The GPR4 subfamily consists of three GPCRs that share significant sequence homology. In addition to GPR4, this subfamily includes OGR1 (GPR68) and T cell death-associated gene 8 (TDAG8) (GPR65). They have been identified to sense extracellular pH after binding H+ ions. A common feature of this family of pH-sensing receptors is their role in the regulation of inflammatory and immune responses and tumorigenesis. In response to extracellular acidification, ph sensing GPRs stimulate a variety of intracellular signalling pathways, including Gs/adenylyl cyclase/cAMP and G13/Rho. Accumulating evidence indicates that the proton-sensing GPRs are inactive or only slightly active at pH 7.8 to 7.6 but become maximally active around pH 6.8. pH sensing GPRs are mainly found in macrophages and other cells of the innate immune system as well as intestinal epithelial cells. Both cell types play a crucial role during the pathogenesis of IBD. Recently we showed that the deletion of GPR4 or OGR1 protects from DSS induced colitis or ameliorates colitis in IL10/pH receptor double knockout mice. Additionally, OGR1 inhibited epithelial cell migration in an acidic environment. We have further evidence that OGR1 Plays a very important tole during the pathogenesis of intestinal fibrosis. In addition we could demonstrate that OGR1 mediates Responses to hypoxia and induces ER stress reactions.This important physiological role of pH sensing GPRs will be further investigated based of the following hypotheses:1) G-protein coupled pH receptors play an important role during responses to ER stress and hypoxia subsequently regulating inflammation.2) G-protein coupled pH receptors (e.g. OGR-1) play an essential role during intestinal fibrosis.3) OGR1/GPR4 on one hand and TDAG8 on the other have antagonistic roles in fine-tuning immune responses.The long term goal will be a better understanding of basic mucosal inflammatory mechanisms and the development of new treatment options (“pH receptor blockers”; “OGR1 antagonists”) for chronic mucosal inflammatory diseases and intestinal fibrosis.