2. Academic Validation
  3. Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis

Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis

  • Mucosal Immunol. 2015 Nov;8(6):1324-38. doi: 10.1038/mi.2015.22.
C M Aherne 1 2,  B Saeedi 2,  C B Collins 2 3,  J C Masterson 2 4,  E N McNamee 1 2,  L Perrenoud 1 2,  C R Rapp 1 2,  V F Curtis 2,  A Bayless 2,  A Fletcher 5,  L E Glover 2,  C M Evans 5,  P Jedlicka 6,  G T Furuta 2 4,  E F de Zoeten 2 3,  S P Colgan 2,  H K Eltzschig 1
Affiliations

Affiliations

  • 1 Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 2 Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 3 Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
  • 4 Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
  • 5 Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 6 Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
PMID: 25850656 DOI: 10.1038/mi.2015.22
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.

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