RANTES mediates TNF-dependent lamina propria mast cell accumulation and barrier dysfunction in neurogenic cystitis

Michael C. Chen, Pavitra Keshavan, Greg D. Gregory, David J. Klumpp*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Barrier dysfunction of the urinary bladder is postulated to contribute to patient morbidity in the bladder inflammatory disease interstitial cystitis (IC). IC is often considered a neurogenic cystitis, but the mechanisms underlying barrier dysfunction are unclear. In murine neurogenic cystitis induced by pseudorabies virus (PRV), we previously observed formation of urothelial lesions characterized by urothelial apoptosis and urothelial discontinuities. Lesion formation was preceded by mast cell trafficking to the lamina propria, and trafficking was mediated by tumor necrosis factor-α (TNF). Here, we found that supernatants of TNF-treated urothelial cultures promoted chemotaxis of bone marrow-derived mast cells in vitro that was blocked by anti-RANTES antibodies but unaffected by anti-TNF antibodies. In vivo, PRV infection of wild-type mice induced RANTES expression in the urothelium that was temporally coincident with lamina propria mast cell accumulation (maximum at days 3-4 following infection) and was not induced in TNF-/- mice, TNFR1/2-/- mice, or mice treated with anti-TNF antibodies. Anti-RANTES antibodies blocked PRV-induced lamina propria mast cell accumulation 56% and reduced the prevalence of animals with detectable lesions 42%, relative to isotype control antibodies. Bladder barrier function was quantified by measuring transepithelial resistance (TER). PRV induced a 49% loss of TER in the presence of control antibodies, but mice treated with anti-RANTES antibodies exhibited reduced TER loss (16%, P < 0.01). These data demonstrate that RANTES plays a key role in the pathogenesis of neurogenic cystitis and suggest that chemokines may represent novel therapeutic targets for IC patients with mast cell-associated disease.

Original languageEnglish (US)
Pages (from-to)F1372-F1379
JournalAmerican Journal of Physiology - Renal Physiology
Volume292
Issue number5
DOIs
StatePublished - May 2007

Keywords

  • Irritable bowel disease
  • Psoriasis
  • Transepithelial resistance

ASJC Scopus subject areas

  • Physiology
  • Urology

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