Aherne, Carole M. and Saeedi, B. and Collins, C.B. and Masterson, Joanne C. and McNamee, Eóin N. and Perrenoud, L. and Rapp, C.R. and Curtis, V.F. and Bayless, A. and Fletcher, A. and Glover, L.E. and Evans, C.M. and Jedlicka, Paul and Furuta, Glenn T. and de Zoeten, Edwin F. and Colgan, S.P. and Eltzschig, Holger K. (2015) Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis. Mucosal immunology, 8 (6). pp. 1324-1338. ISSN 1935-3456

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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 adenosinemediated 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 (Adora2bfl/flVeCadCre þ ) or intestinal epithelia (Adora2bfl/flVillinCre þ ) 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.

Item Type:	Article
Keywords:	Epithelial-specific; A2B adenosine receptor; signaling; protects; colonic epithelial barrier; acute colitis; colitis;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	12484
Identification Number:	https://doi.org/10.1038/mi.2015.22
Depositing User:	Joanne Masterson
Date Deposited:	26 Feb 2020 16:53
Journal or Publication Title:	Mucosal immunology
Publisher:	Springer Nature
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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