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 (Adora2bfl/flVeCadCre+) or intestinal epithelia (Adora2bfl/flVillinCre+) 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.

Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

“…A 2B AR mediated the protective effect of adenosine in intestinal inflammation by promoting epithelial barrier (Aherne et al, 2015). Our results also indicate that intracellular calcium mediates the antiproliferative effect of A 2B AR activation on NHEK, with no involvement of cAMP.…”

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

“…During the course of mucosal inflammation, increasing expression of NTPDases leads to ATP breakdown and release of extracellular adenosine, which has been implicated as an endogenous protective reagent in IBD 43. A2A and A2B receptors were suggested to contribute to the anti‐inflammatory action of adenosine 44, 45, 46. We found here that ILC3s express high levels of A2A receptor, and activation of the A2A receptor promotes IL‐22 production from ILC3s.…”

Novel therapeutic concepts for inflammatory bowel disease—from bench to bedside

“…Here, the production of adenosine is considered to provide a potent anti-inflammatory and tissue-protective function during mucosal inflammation [4]. Adenosine synthesis involved molecules such as the ectonuceotidases CD39 and CD73, as well as adenosine receptor molecules are critical for the inflammation-dampening effects of adenosine [5, 6]. In the case of adenosine, its simultaneous action in immune response suppression as a “metabokine,” re-directing the adaptive T cell-mediated immune response, indicates the strong interrelation between inflammation and tissue metabolism.…”