Enteric glial adenosine 2B receptor signaling mediates persistent epithelial barrier dysfunction following acute DSS colitis

Intestinal epithelial barrier function is compromised in inflammatory bowel disease and barrier dysfunction contributes to disease progression. Extracellular nucleotides/nucleosides generated in gut inflammation may regulate barrier function through actions on diverse cell types. Enteric glia modulate extracellular purinergic signaling and exert pathophysiological effects on mucosal permeability. These glia may regulate inflammation with paracrine responses, theoretically mediated via adenosine 2B receptor (A(2B)R) signaling. As the cell-specific roles of A(2B)Rs in models of colitis and barrier dysfunction are unclear, we studied glial A(2B)Rs in acute dextran sodium sulfate (DSS) colitis. We performed and validated conditional ablation of glial A(2B)Rs in Sox10(CreERT2+/−);Adora2b(f/f) mice. Overt intestinal disease activity indices in DSS-colitis were comparable between Sox10(CreERT2+/–);Adora2b(f/f) mice and littermate controls. However, ablating glial A(2B)Rs protected against barrier dysfunction following acute DSS-colitis. These benefits were associated with the normalization of tight junction protein expression and localization including claudin-1, claudin-8, and occludin. Glial A(2B)R signaling increased levels of proinflammatory mediators in the colon and cell-intrinsic regulation of genes including Csf3, Cxcl1, Cxcl10, and Il6. Our studies show that glial A(2B)R signaling exacerbates immune responses during DSS-colitis and that this adenosinergic cell-specific mechanism contributes to persistent gut epithelial barrier dysfunction.