title: Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis.
abstract: Central to inflammatory bowel disease (IBD) pathogenesis is loss of mucosal barrier function. Emerging evidence implicates extracellular adenosine signaling in attenuating mucosal inflammation. We hypothesized that adenosine-mediated protection from intestinal barrier dysfunction involves tissue-specific signaling through the A2B adenosine receptor (Adora2b) at the intestinal mucosal surface. To address this hypothesis, we combined pharmacologic studies and studies in mice with global or tissue-specific deletion of the Adora2b receptor. Adora2b(-/-) mice experienced a significantly heightened severity of colitis, associated with a more acute onset of disease and loss of intestinal epithelial barrier function. Comparison of mice with Adora2b deletion on vascular endothelial cells (Adora2b(fl/fl)VeCadCre(+)) or intestinal epithelia (Adora2b(fl/fl)VillinCre(+)) revealed a selective role for epithelial Adora2b signaling in attenuating colonic inflammation. In vitro studies with Adora2b knockdown in intestinal epithelial cultures or pharmacologic studies highlighted Adora2b-driven phosphorylation of vasodilator-stimulated phosphoprotein (VASP) as a specific barrier repair response. Similarly, in vivo studies in genetic mouse models or treatment studies with an Adora2b agonist (BAY 60-6583) recapitulate these findings. Taken together, our results suggest that intestinal epithelial Adora2b signaling provides protection during intestinal inflammation via enhancing mucosal barrier responses.
authors: Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: C M
authors: CM
authors: Aherne
authors: Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: B
authors: B
authors: Saeedi
authors: Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
authors: C B
authors: CB
authors: Collins
authors: Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
authors: J C
authors: JC
authors: Masterson
authors: Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: E N
authors: EN
authors: McNamee
authors: Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: L
authors: L
authors: Perrenoud
authors: Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: C R
authors: CR
authors: Rapp
authors: Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: V F
authors: VF
authors: Curtis
authors: Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: A
authors: A
authors: Bayless
authors: Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: A
authors: A
authors: Fletcher
authors: Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: L E
authors: LE
authors: Glover
authors: Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: C M
authors: CM
authors: Evans
authors: Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: P
authors: P
authors: Jedlicka
authors: Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
authors: G T
authors: GT
authors: Furuta
authors: Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
authors: E F
authors: EF
authors: de Zoeten
authors: Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: S P
authors: SP
authors: Colgan
authors: Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors: H K
authors: HK
authors: Eltzschig
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D003092:Colitis / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D043704:Receptor, Adenosine A2B