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

• Published in: Mucosal immunology Vol. 8; no. 6; pp. 1324 - 1338
• Main Authors: Aherne, C M, Saeedi, B, Collins, C B, Masterson, J C, McNamee, E N, Perrenoud, L, Rapp, C R, Curtis, V F, Bayless, A, Fletcher, A, Glover, L E, Evans, C M, Jedlicka, P, Furuta, G T, de Zoeten, E F, Colgan, S P, Eltzschig, H K
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2015; Elsevier Limited
• Subjects: 631/250/347; 631/80/86; 692/699/1503/1581/1392/1388; Acute Disease; Allergology; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Colitis - metabolism; Colitis - pathology; Disease Models, Animal; Epithelial Cells - metabolism; Epithelial Cells - pathology; Flow Cytometry; Fluorescent Antibody Technique; Gastroenterology; Immunology; In Situ Nick-End Labeling; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Adenosine A2B - metabolism; Signal Transduction - physiology
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2015.22

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.