Neuroepithelial control of mucosal inflammation in acute cystitis

Scientific Reports
Daniel S C ButlerC Svanborg

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 therape...Continue Reading

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Citations

Jun 11, 2019·PLoS Pathogens·Ines AmbiteCatharina Svanborg
Feb 12, 2020·Sexually Transmitted Diseases·Caroline M MitchellDavid N Fredricks
Sep 26, 2020·Frontiers in Physiology·Hana StarobovaIrina Vetter
Aug 18, 2020·The Journal of Investigative Dermatology·Killian L'HerondelleRaphaele Le Garrec
Jun 17, 2021·Nature Reviews. Urology·Ines AmbiteCatharina Svanborg
Sep 2, 2021·European Urology Open Science·Björn WulltCatharina Svanborg

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Methods Mentioned

BETA
ELISA
electrophoretic mobility shift assay
Assay
confocal
fluorescence microscopy

Software Mentioned

Ingenuity Pathway Analysis
Partek Express
ImageJ
ToppGene 66

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