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Pannexin 1 involvement in bladder dysfunction in a multiple sclerosis model

Negoro, H;Lutz, SE;Liou, LS;Kanematsu, A;Ogawa, O;Scemes, E;Suadicani, SO;

Bladder dysfunction is common in Multiple Sclerosis (MS) but little is known of its pathophysiology. We show that mice with experimental autoimmune encephalomyelitis (EAE), a MS model, have micturition dysfunction and altered expression of genes associated with bladder mechanosensory, transduction and signaling systems including pannexin 1 (Panx1) and Gja1 (encoding connexin43, referred to here as Cx43). EAE mice with Panx1 depletion (Panx1(-/-)) displayed similar neurological deficits but lesser micturition dysfunction compared to Panx1(+/+) EAE. Cx43 and IL-1 upregulation in Panx1(+/+) EAE bladder mucosa was not observed in Panx1(-/-) EAE. In urothelial cells, IL-1 stimulation increased Cx43 expression, dye-coupling, and p38 MAPK phosphorylation but not ERK1/2 phosphorylation. SB203580 (p38 MAPK inhibitor) prevented IL-1-induced Cx43 upregulation. IL-1 also increased IL-1, IL-1R-1, PANX1 and CASP1 expression. Mefloquine (Panx1 blocker) reduced these IL-1 responses. We propose that Panx1 signaling provides a positive feedback loop for inflammatory responses involved in bladder dysfunction in MS.