Neuroepithelial control of mucosal inflammation in acute cystitis

Daniel S.C. Butler, Ines Ambite, Karoly Nagy, Caterina Cafaro, Abdulla Ahmed, Aftab Nadeem, Nina Filenko, Thi Hien Tran, Karl Erik Andersson, Björn Wullt, Manoj Puthia, Catharina Svanborg

Research output: Contribution to journalArticlepeer-review


The nervous system is engaged by infection, indirectly through inflammatory cascades or directly, by bacterial attack on nerve cells. Here we identify a neuro-epithelial activation loop that participates in the control of mucosal inflammation and pain in acute cystitis. We show that infection activates Neurokinin-1 receptor (NK1R) and Substance P (SP) expression in nerve cells and bladder epithelial cells in vitro and in vivo in the urinary bladder mucosa. Specific innate immune response genes regulated this mucosal response, and single gene deletions resulted either in protection (Tlr4−/− and Il1b−/− mice) or in accentuated bladder pathology (Asc−/− and Nlrp3−/− mice), compared to controls. NK1R/SP expression was lower in Tlr4−/− and Il1b−/− mice than in C56BL/6WT controls but in Asc−/− and Nlrp3−/− mice, NK1R over-activation accompanied the exaggerated disease phenotype, due, in part to transcriptional de-repression of Tacr1. Pharmacologic NK1R inhibitors attenuated acute cystitis in susceptible mice, supporting a role in disease pathogenesis. Clinical relevance was suggested by elevated urine SP levels in patients with acute cystitis, compared to patients with asymptomatic bacteriuria identifying NK1R/SP as potential therapeutic targets. We propose that NK1R and SP influence the severity of acute cystitis through a neuro-epithelial activation loop that controls pain and mucosal inflammation.

Original languageEnglish
Article number11015
Pages (from-to)1-15
JournalScientific Reports
Publication statusPublished - 2018 Jul 20

Subject classification (UKÄ)

  • Immunology in the medical area


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