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Coordination of ENT2-dependent adenosine transport and signaling dampens mucosal inflammation
Carol M. Aherne, … , Michael R. Blackburn, Holger K. Eltzschig
Carol M. Aherne, … , Michael R. Blackburn, Holger K. Eltzschig
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e121521. https://doi.org/10.1172/jci.insight.121521.
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Research Article Gastroenterology

Coordination of ENT2-dependent adenosine transport and signaling dampens mucosal inflammation

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Abstract

Intestinal epithelial barrier repair is vital for remission in inflammatory bowel disease (IBD). Extracellular adenosine signaling has been implicated in promoting restoration of epithelial barrier function. Currently, no clinically approved agents target this pathway. Adenosine signaling is terminated by uptake from the extracellular space via equilibrative nucleoside transporters (ENTs). We hypothesized that ENT inhibition could dampen intestinal inflammation. Initial studies demonstrated transcriptional repression of ENT1 and ENT2 in IBD biopsies or in murine IBD models. Subsequent studies in mice with global Ent1 or Ent2 deletion revealed selective protection of Ent2–/– mice. Elevated intestinal adenosine levels in conjunction with abolished protection following pharmacologic blockade of A2B adenosine receptors implicate adenosine signaling as the mechanism of gut protection in Ent2–/– mice. Additional studies in mice with tissue-specific deletion of Ent2 uncovered epithelial Ent2 as the target. Moreover, intestinal protection provided by a selective Ent2 inhibitor was abolished in mice with epithelium-specific deletion of Ent2 or the A2B adenosine receptor. Taken together, these findings indicate that increased mucosal A2B signaling following repression or deletion of epithelial Ent2 coordinates the resolution of intestinal inflammation. This study suggests the presence of a targetable purinergic network within the intestinal epithelium designed to limit tissue inflammation.

Authors

Carol M. Aherne, Colm B. Collins, Caroline R. Rapp, Kristine E. Olli, Loni Perrenoud, Paul Jedlicka, Jessica L. Bowser, Tingting W. Mills, Harry Karmouty-Quintana, Michael R. Blackburn, Holger K. Eltzschig

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Figure 7

Adenosine generation and signaling play a central role in the protective effect of Ent2 loss in experimental colitis.

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Adenosine generation and signaling play a central role in the protective...
(A) Sex-, age-, and weight-matched Ent2-deficient mice (Ent2–/–) or WT controls (Ent2+/+, mice on a B6/129 background) were exposed to DSS for 6 days, followed by water for 24 hours. Colonic lavage was performed on terminally anesthetized mice with nucleoside preserving cocktail. Adenosine concentration in the lavage fluid was determined by HPLC and normalized to protein content. Results are shown as mean ± SEM, n = 6 mice/group, and are representative of 2 independent experiments. (B–D) Sex-, age-, and weight-matched Ent2-deficient mice (Ent2–/–, mice on a B6/129 background) were treated with an A2B receptor–specific antagonist (PSB 1115, 1 mg/kg/mouse, oral gavage) on days –1, 0, 2, 4, and 6 of DSS colitis. (B) Mice were weighed daily. Results are presented as percentage of bodyweight on day 0. (C) Histological analysis of whole colon harvested on day 7 after DSS. Scores were provided by a pathologist blinded to the groups and the study. (D) Representative histological sections from whole colon harvested on day 7 after DSS (Bar represents 100 μm; images acquired at ×10). Results are presented as mean ± SEM, n = 7–8 mice/treatment group, from 1 independent experiment. Two-way ANOVA with post hoc Bonferroni’s t test was used to determine statistical weight change; in all other cases, paired Student’s t test was used. *P < 0.05.

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