The Molecular Basis of Acute Cystitis; IL-1beta and Inflammasome Dysregulation

Despite its prevalence and deleterious effects, acute cystitis has remained a molecular enigma. We now define acute cystitis as a hyper-inflammatory condition of the urinary bladder, driven by IL-1b over-activation in inflammasome-deficient hosts. IL-1b was selected for study as >85% of acute cystitis isolates triggered an IL-1b response in human bladder epithelial cells. IL-1b was identified as an essential innate immune response arbitrator, as IL-1b^-/- mice were unresponsive to infection, in contrast to Asc^-/- and Nlrp3^-/- mice, where inflammasome dysregulation caused a dramatic acute cystitis phenotype, with hyper-activation of IL-1b and IL-1b-dependent gene expression. The IL-1b dependence of acute cystitis was confirmed by IL-1b receptor antagonist therapy, which prevented acute cystitis in susceptible mice. In the absence of a functional inflammasome, IL-1b was processed via an alternative mechanism, involving the Mmp7 metalloproteinase, which was strongly upregulated in pathological bladder epithelium. MMP-7 was shown to cleave IL-1b in vitro and an MMP inhibitor attenuated disease in Asc^-/- mice. Clinical relevance was demonstrated by increased urine IL-1b and Mmp7 levels in patients with acute cystitis, compared to patients with asymptomatic bacteriuria or healthy controls. These results provide, for the first time, a comprehensive molecular framework for the pathogenesis of acute cystitis, raising the possibility that IL-1b immunotherapy might be used to prevent pathology in patients prone to acute cystitis. As effects of inflammasome dysregulation were bladder specific, effects on acute pyelonephritis susceptibility would not be expected to occur.