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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<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>in the urinary bladder mucosa. Specific innate immune response genes regulated this mucosal response, and single gene deletions resulted either in protection (<jats:italic>Tlr4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>and<jats:italic>Il1b<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice) or in accentuated bladder pathology (<jats:italic>Asc<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>and<jats:italic>Nlrp3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice), compared to controls. NK1R\/SP expression was lower in<jats:italic>Tlr4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>and<jats:italic>Il1b<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice than in C56BL\/6WT controls but in<jats:italic>Asc<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>and<jats:italic>Nlrp3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice, NK1R over-activation accompanied the exaggerated disease phenotype, due, in part to transcriptional de-repression of<jats:italic>Tacr1<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1038\/s41598-018-28634-0","type":"journal-article","created":{"date-parts":[[2018,7,16]],"date-time":"2018-07-16T11:29:41Z","timestamp":1531740581000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Neuroepithelial control of mucosal inflammation in acute cystitis"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6717-545X","authenticated-orcid":false,"given":"Daniel S. 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