P041 - GLIAL CONNEXIN-43 REGULATES NEURO-IMMUNE INTERACTIONS IN THE MOUSE COLON
(Room Poster Hall)
19 Jan 18
5:30 PM
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7:00 PM
Tracks:
Clinical and Research Challenges
The enteric nervous system regulates gut reflexes. Our prior data show that enteric glia regulate the activity and survival of enteric neurons in health and disease through mechanisms that involve the release of mediators through connexin-43 (Cx43) hemichannels. Given that immune cells express receptors for glial mediators released via Cx43, we hypothesized that enteroglial signaling involving Cx43 contributes to immune cell recruitment. Cx43 was ablated in glial cells in hGFAP::CreERT2+/–/Cx43f/f mice (TG) and we assessed the effect of acute and chronic inflammation driven by dextran sodium sulfate (DSS). Acute colitis (aDSS) was induced by 2% DSS in drinking water for 1 week while chronic colitis (cDSS) was driven by intermittent exposure to DSS (1 week on/ 1 off) for 3 weeks. Body weight and macroscopic damage were used to assess the inflammation, and immunohistochemistry was used to determine numbers of neurons, glia and immune cells. Cytokine profiles were assayed by plate array. Our results show that DSS caused weight loss and macroscopic tissue damage, but not significant neurodegeneration in the myenteric plexus of either TG mice or littermate controls (wt). cDSS drove a significant increase in CD45+ and CD68+ immune cells in wt mice (P=0.013 and 0.013, 2-way ANOVA, water-DSS comparison) that was not observed in TG animals (P=0.127 and 0.982, 2-way ANOVA, water-DSS comparison). In addition, loss of enteroglial Cx43 affected the colonic production of cytokines: about 2-fold reduction of IL-2, IL-7, IL-9, and MIP-1a (P<0.05, 2-way ANOVA, genotype comparison), and protected against the aDSS-induced increase of M-CSF in the transgenic animals [P=0.030 (wt) vs 0.904 (TG), 2-way ANOVA, water-DSS comparison]. Together, our findings show that enteric glia contribute to immune cell recruitment during the chronic phase of inflammation through mechanisms that involve Cx43. These novel findings could be used to design novel therapeutics for inflammatory bowel disease.