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

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2022

Mucosal Immunol. 2022 May;15(5):964-976. doi: 10.1038/s41385-022-00550-7. Epub 2022 Jul 22.

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

Vladimir Grubišić, Vedrana Bali, David E Fried, Holger K Eltzschig, Simon C Robson, Michelle S Mazei-Robison, Brian D Gulbransen

Department of Biomedical Sciences and Center for Biomedical Innovation, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, 11568, USA. Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, 48824, USA. McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. Division of Gastroenterology, Departments of Medicine and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. Department of Physiology and Neuroscience program, Michigan State University, East Lansing, MI, 48824, USA.

Service type: Knockout mice

Abstract

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 (A2BR) signaling. As the cell-specific roles of A2BRs in models of colitis and barrier dysfunction are unclear, we studied glial A2BRs in acute dextran sodium sulfate (DSS) colitis. We performed and validated conditional ablation of glial A2BRs in Sox10CreERT2+/-;Adora2bf/f mice. Overt intestinal disease activity indices in DSS-colitis were comparable between Sox10CreERT2+/-;Adora2bf/f mice and littermate controls. However, ablating glial A2BRs 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 A2BR 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 A2BR signaling exacerbates immune responses during DSS-colitis and that this adenosinergic cell-specific mechanism contributes to persistent gut epithelial barrier dysfunction.

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