Pannexin 1 involvement in bladder dysfunction in a multiple sclerosis model

Abstract

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-1β upregulation in Panx1+/+ EAE bladder mucosa was not observed in Panx1−/− EAE. In urothelial cells, IL-1β stimulation increased Cx43 expression, dye-coupling, and p38 MAPK phosphorylation but not ERK1/2 phosphorylation. SB203580 (p38 MAPK inhibitor) prevented IL-1β-induced Cx43 upregulation. IL-1β also increased IL-1β, IL-1R-1, PANX1 and CASP1 expression. Mefloquine (Panx1 blocker) reduced these IL-1β responses. We propose that Panx1 signaling provides a positive feedback loop for inflammatory responses involved in bladder dysfunction in MS.