Journal
PLOS PATHOGENS
Volume 12, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1005848
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Funding
- Swedish Research Council
- Medical Faculty (Lund University)
- Swedish Cancer Society
- Sharon D Lund
- Soderberg Foundation
- Osterlund Foundation
- Anna-Lisa and Sven-Erik Lundgren Foundation
- Maggie Stephens Foundation
- Inga-Britt and Arne Lundberg Foundation
- HJ Forssman Foundation
- Royal Physiographic Society
- Network of Excellence: EuroPathoGenomics
- European Urological Scholarship Program [S-03-2013]
- Deutsche Forschungsgemeinschaft [MI471/6-1]
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Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1 beta)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1 beta processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1 beta processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7-(MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc(-/-) and Nlrp3(-/-) mice. The resulting IL-1 beta hyper-activation loop included a large number of IL-1 beta-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc(-/-) mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1 beta and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man.
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