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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 1

Ent 1 and Ent2 expression is repressed in IBD and murine colitis.

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Ent 1 and Ent2 expression is repressed in IBD and murine colitis.
(A an...
(A and B) cDNA from control, active Crohn’s disease, or ulcerative colitis biopsies (Origene) was probed with specific primers (QuantiTect, QIAGEN) for human ENT1, ENT2, and β-actin. ENT1 and ENT2 levels were normalized to β-actin and are expressed as fold change relative to control biopsies. n = 5 control, n = 17–21 Crohn’s disease, and n = 18–20 ulcerative colitis patients. (C–F) Sex-, age-, and weight-matched C57BL/6 mice were exposed to DSS. After 3, 6, or 7 days, whole-colon (C and D) or mucosal scrapings from the proximal and distal colon (E and F) were harvested, and total RNA was extracted. TaqMan RT-PCR for Ent1, Ent2, and 18s was performed. (C–F) mRNA transcript levels were calculated relative to 18s and are expressed as the fold change compared with water-treated (H2O) mice. In all cases data are displayed as mean ± SEM. Results in C and D represent n = 5–10 mice/group from 2 independent experiments. Results in E and F represent 6–8 mice/group from 2 independent experiments. One-way ANOVA with post hoc Dunnett’s multiple-comparisons test was performed to determine statistical differences compared with control or water. *P < 0.05.

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