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Neuroepithelial control of mucosal inflammation in acute cystitis

Butler, Daniel S.C. LU ; Ambite, Ines LU ; Nagy, Karoly LU ; Cafaro, Caterina LU ; Ahmed, Abdulla; Nadeem, Aftab LU ; Filenko, Nina LU ; Tran, Thi Hien LU ; Andersson, Karl Erik LU and Wullt, Björn LU , et al. (2018) In Scientific Reports 8(1).
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.... (More)

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.

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Scientific Reports
volume
8
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85050646838
ISSN
2045-2322
DOI
10.1038/s41598-018-28634-0
language
English
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yes
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7d899dfd-ed60-4db6-8a09-95ab755010da
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2018-08-15 14:30:21
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2019-03-26 16:56:13
@article{7d899dfd-ed60-4db6-8a09-95ab755010da,
  abstract     = {<p>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<sup>−/−</sup> and Il1b<sup>−/−</sup> mice) or in accentuated bladder pathology (Asc<sup>−/−</sup> and Nlrp3<sup>−/−</sup> mice), compared to controls. NK1R/SP expression was lower in Tlr4<sup>−/−</sup> and Il1b<sup>−/−</sup> mice than in C56BL/6WT controls but in Asc<sup>−/−</sup> and Nlrp3<sup>−/−</sup> 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.</p>},
  articleno    = {11015},
  author       = {Butler, Daniel S.C. and Ambite, Ines and Nagy, Karoly and Cafaro, Caterina and Ahmed, Abdulla and Nadeem, Aftab and Filenko, Nina and Tran, Thi Hien and Andersson, Karl Erik and Wullt, Björn and Puthia, Manoj and Svanborg, Catharina},
  issn         = {2045-2322},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Neuroepithelial control of mucosal inflammation in acute cystitis},
  url          = {http://dx.doi.org/10.1038/s41598-018-28634-0},
  volume       = {8},
  year         = {2018},
}