title: G Protein-coupled pH-sensing Receptor OGR1 Is a Regulator of Intestinal Inflammation.
abstract: BACKGROUND
  A novel family of proton-sensing G protein-coupled receptors, including OGR1, GPR4, and TDAG8, was identified to be important for physiological pH homeostasis and inflammation. Thus, we determined the function of proton-sensing OGR1 in the intestinal mucosa.
  
  
  METHODS
  OGR1 expression in colonic tissues was investigated in controls and patients with IBD. Expression of OGR1 upon cell activation was studied in the Mono Mac 6 (MM6) cell line and primary human and murine monocytes by real-time PCR. Ogr1 knockout mice were crossbred with Il-10 deficient mice and studied for more than 200 days. Microarray profiling was performed using Ogr1 and Ogr1 (WT) residential peritoneal macrophages.
  
  
  RESULTS
  Patients with IBD expressed higher levels of OGR1 in the mucosa than non-IBD controls. Treatment of MM6 cells with TNF, led to significant upregulation of OGR1 expression, which could be reversed by the presence of NF-κB inhibitors. Kaplan-Meier survival analysis showed a significantly delayed onset and progression of rectal prolapse in female Ogr1/Il-10 mice. These mice displayed significantly less rectal prolapses. Upregulation of gene expression, mediated by OGR1, in response to extracellular acidification in mouse macrophages was enriched for inflammation and immune response, actin cytoskeleton, and cell-adhesion gene pathways.
  
  
  CONCLUSIONS
  OGR1 expression is induced in cells of human macrophage lineage and primary human monocytes by TNF. NF-κB inhibition reverses the induction of OGR1 expression by TNF. OGR1 deficiency protects from spontaneous inflammation in the Il-10 knockout model. Our data indicate a pathophysiological role for pH-sensing receptor OGR1 during the pathogenesis of mucosal inflammation.
authors: *Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland; †Institute of Physiology, University of Zürich, Zürich, Switzerland; ‡Department of Clinical Pharmacology and Toxicology, University Hospital Zürich, Zürich, Switzerland; and §Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Cheryl
authors: C
authors: de Vallière
authors: Yu
authors: Y
authors: Wang
authors: Jyrki J
authors: JJ
authors: Eloranta
authors: Solange
authors: S
authors: Vidal
authors: Ieuan
authors: I
authors: Clay
authors: Marianne R
authors: MR
authors: Spalinger
authors: Irina
authors: I
authors: Tcymbarevich
authors: Anne
authors: A
authors: Terhalle
authors: Marie-Gabrielle
authors: MG
authors: Ludwig
authors: Thomas
authors: T
authors: Suply
authors: Michael
authors: M
authors: Fried
authors: Gerd A
authors: GA
authors: Kullak-Ublick
authors: Isabelle
authors: I
authors: Frey-Wagner
authors: Michael
authors: M
authors: Scharl
authors: Klaus
authors: K
authors: Seuwen
authors: Carsten A
authors: CA
authors: Wagner
authors: Gerhard
authors: G
authors: Rogler
mesh_terms: D000136:Acid-Base Equilibrium / Q000502:physiology; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000473:pathology; D016753:Interleukin-10; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: C486281:GPR68 protein, human; C525539:GPR68 protein, mouse; C556062:IL10 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016753:Interleukin-10