Enteroglial adenosine A2B receptor signaling contributes to local cytokine production and delays functional recovery following acute inflammation in the mouse colon

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Glial cells in the enteric nervous system (ENS) contribute to regulation of gut functions by modulating neural reflexes that control motility and secretion. Intestinal inflammation leads to gut dysfunction by inducing neuroplasticity in the ENS. The mechanisms that control local inflammation in the ENS are poorly understood. Resolution coincides with a thousand‐fold increase in adenosine production. Enteric glia express functional adenosine A2B receptors (A2BRs), but the role of glial activation by adenosine is unknown. We hypothesized that enteroglial A2BRs play a role in the progression of the ENS neuroinflammation. We tested our hypothesis by utilizing molecular genetics to ablate A2BRs in glial cells in Sox10::CreERT2+/−/A2BRf/f mice and acute colitis was induced by 2% dextran sodium sulfate (DSS) in drinking water for 7 days. We performed experiments 1 and 3 weeks post DSS treatment to assess the peak and recovery of inflammation. The degree of inflammation was evaluated by body weight change, macroscopic tissue damage, and immunohistochemistry to examine cellular changes in the ENS. Colonic epithelial functions and cytokine/chemokine production were assayed by Ussing chambers and plate array. At peak‐inflammation weight loss, macroscopic tissue damage, and infiltration of CD45+ cells at the level of the myenteric plexus were comparable between the Sox10::CreERT2+/−/A2BRf/f mice and their littermate controls (A2BRf/f). During the recovery, colon wall permeability of DSS‐treated A2BRf/f animals was significantly increased in comparison to their water treated controls, but not in colons from the Sox10::CreERT2+/−/A2BRf/f mice (P = 0.03 and 0.72, respectively, 2‐way ANOVA, water‐to‐DSS comparison). In addition, the ablation of enteroglial A2BRs protected against the DSS‐induced increase in colonic production of cytokines/chemokines at the peak of inflammation (G‐CSF, IL‐1a, IL‐6, IP‐10, MIG), during recovery (IL‐17), or both phases (eotaxin‐1, KC) [P ≤ 0.07 (A2BRf/f) vs P > 0.3 (Sox10::CreERT2+/−/A2BRf/f), 2‐way ANOVA, water‐to‐DSS comparison]. Together, our findings indicate that glial A2BR signaling modulates endogenous immune responses during acute colitis. Glial‐immune interactions mediated downstream of glial A2BR signaling could contribute to gut dysfunction following inflammation. These novel findings could be used in the design of new therapeutics for inflammatory bowel disease.Support or Funding InformationDr. Gulbransen's research is currently supported by grants from the Crohn's and Colitis Foundation (CCF; Senior Research Award) and the National Institutes of Health (NIH; RO1DK103723).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.