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

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.

Up-regulation of LCN2 in the anterior cingulate cortex contributes to neural injury-induced chronic pain

“…An internal stainless-steel injector attached to a 10 μl syringe (Hamilton) and an infusion pump (micro 4, WPI, USA) was inserted into the guide cannula and used to infuse LCN2 mAb (0.5 μg/300 nl/day, R&D system), Isotype mAb (0.5 μg/300 nl/day, R&D system), rmLCN2 (1 μg/300 nl/day, R&D system) or ACSF (300 nl/day) into the right ACC at a flow rate of 150 nl/min. Isotype mAb is widely used as an isotype control in control experiments of mice ( Shashidharamurthy et al, 2013 ; Deczkowska et al, 2021 ; Grubišić et al, 2022 ). Mice were administrated with LCN2 mAb, Isotype mAb, or ACSF starting at the 8 days after SNI treatment until the 14 days.…”

Stimulator of interferon genes (STING) expression in the enteric nervous system and contributions of glial STING in disease

“…[15][16][17] In turn, these glial cells respond to gut dysbiosis and interact with immune cells and the mucosal barrier to produce varying proinflammatory and protective effects. [18][19][20][21] Characterized mechanisms of glial-microbe signaling involve S100β and pattern recognition receptors of the toll-like receptor family; however, the mechanisms whereby glia monitor the gut microbiota and initiate functional responses remain mostly uncharacterized.…”

IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer

“…However, accumulating evidence highlights EGCs as crucial mediators of interactions not only among enteric neurons but also intestinal epithelium, enteroendocrine cells, and immune cells (Thomasi and Gulbransen, 2023;Prochera and Rao, 2023;Bohórquez et al, 2014;Seguella and Gulbransen, 2021). Of particular interest is their significant role in modulating immune responses in various intestinal diseases (Ibiza et al, 2016;Progatzky et al, 2021;Grubišić et al, 2020Grubišić et al, , 2022. Being highly responsive to inflammatory mediators, including ATP, IL-1 cytokines, or LPS, EGCs are rapidly activated during intestinal diseases.…”

“…Indeed, accumulating evidence highlights EGCs as crucial mediators of interactions among enteric neurons, intestinal epithelium, enteroendocrine cells, and immune cells [7][8][9][10] . Of particular interest is their significant role in modulating immune responses in various intestinal diseases [11][12][13][14] . In this regard, we recently demonstrated that EGCs significantly affect macrophage recruitment and differentiation in a murine model of acute intestinal inflammation such as post-operative ileus 15,16 .…”