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.
Highlights
Infections are accompanied by characteristic symptoms from the site of infection and by general malaise, in case of systemic involvement
We address if acute cystitis strains activate a neuropeptide- and neuropeptide receptor response in the urinary bladder mucosa and if the genes that regulate acute cystitis severity control nerve cell activation
Epithelial cells are essential for the mucosal barrier function and, when activated, they recruit a range of resident and circulating cells, to execute the defense
Summary
Infections are accompanied by characteristic symptoms from the site of infection and by general malaise, in case of systemic involvement. As virulence factors engage specific receptors on nerve cells, bacteria activate ion fluxes, leading to nerve cell activation[5] Examples of such interactions include recognition of Lipopolysaccharide (LPS) by Toll like receptor-4 (TLR-4) and of Shiga toxin by glycolipid receptors[6,7]. In addition to painful urination (dysuria), characteristic clinical symptoms include urgency and frequency of urination, caused by activation of the micturition reflex and contractions of the bladder detrusor muscle[11]. This symptom profile indicates that the nervous system is engaged in the pathogenesis of acute cystitis[12] but molecular determinants of this process have not been defined. The study was prompted by the characteristic symptoms of acute cystitis and by preliminary evidence of neuropeptide receptor activation in patients with bacteriuria
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