Neuroepithelial control of mucosal inflammation in acute cystitis

Abstract

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.

PAR2, Keratinocytes, and Cathepsin S Mediate the Sensory Effects of Ciguatoxins Responsible for Ciguatera Poisoning

“…Both KCs and sensory neurons express the SP neurokinin-1 receptor and can release SP in an autocrine manner (Bae et al, 1999;Tang et al, 2007). SP released from neurons could elicit SP release from KCs as previously shown in other contexts (Butler et al, 2018). Vice versa, KC mediators other than SP, including proinflammatory cytokines and nerve GF, could potentiate P-CTX-2-induced SP release from sensory neurons (Wei et al, 2012).…”

Fimbriae reprogram host gene expression – Divergent effects of P and type 1 fimbriae

“…The response was reproduced in human bladder epithelial cells, where NK1R and SP protein levels were increased in vitro after E . coli 83972 fim infection [48] ( Fig 7C ). Furthermore, the purified FimCH complex stimulated NK1R and SP expression in human bladder epithelial cells ( Fig 7D ), suggesting that type 1 fimbriae contribute to the activation of neuropeptides and neuropeptide receptors in an adhesin-dependent manner.…”

Receptor pharmacology and other relevant factors in lower urinary tract pathology under a functional and toxicological approach: Instrument to better manage antimicrobials therapy

“…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 the NK1R and SP in luence the severity of acute cystitis through a neuro-epithelial activation loop that controls pain and mucosal in lammation' [9].…”