Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets

PLoS Pathogens

Daniel S. C. Butler¹  Björn Wullt¹  Manoj Puthia¹  Caterina Cafaro¹  Gustav Rydström¹  Karoly Nagy¹  Aftab Nadeem¹  Catharina Svanborg¹  Nina A. Filenko¹  Ines Ambite¹  Thomas Miethke² 

[1] Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Lund University, Lund, Sweden;Institute of Medical Microbiology and Hygiene, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany

关键词: Bladder;    Cystitis;    Neutrophils;    Urine;    Mouse models;    Inflammation;    Gene expression;    Inflammasomes;   

DOI  :  10.1371/journal.ppat.1005848

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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-1β)-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-1β 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-1β 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-1β hyper-activation loop included a large number of IL-1β-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-1β 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.

【 授权许可】

CC BY