Urothelial lesion formation is mediated by TNFR1 during neurogenic cystitis
Abstract
Interstitial cystitis (IC) is a chronic bladder inflammatory disease of unknown etiology that shares similarities with Crohn's disease and psoriasis. IC, often regarded as a neurogenic cystitis, is associated with urothelial lesions that likely compromise the bladder permeability barrier and thereby contribute to patient morbidity. Here, we use a murine model of neurogenic cystitis to investigate the mechanism of urothelial lesion formation and find that urothelial apoptosis induces formation of lesions. Lesions formed in wild-type mice but not in mice deficient in TNF, TNF receptors, or mast cells. In urothelial cultures, only siRNAs targeting TNFR1, but not TNFR2, blocked TNF-induced apoptosis, indicating a primary role for TNFR1. Trans-epithelial resistance, a measure of bladder barrier function, decreased during neurogenic cystitis in wild-type and TNFR2(-/-) mice but was stabilized in TNF(-/-) mice. Anti-TNF antibodies both altered bladder mast cell localization and stabilized barrier function. Based on these findings, we conclude that mast cell activation and release of TNF drive urothelial apoptosis and lesion formation in a murine neurogenic cystitis model, and we hypothesize that anti-TNF therapy may stabilize bladder ...Continue Reading
References
Tumor necrosis factor promotes differential trafficking of bladder mast cells in neurogenic cystitis
Citations
Ca(2+)/calmodulin-dependent protein kinase II is associated with pelvic pain of neurogenic cystitis.
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