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Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis.
MedLine Citation:
PMID:  19106986     Owner:  NLM     Status:  In-Data-Review    
Introduction: Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and interleukin-1 receptor 1 (IL-1R1) signalling pathway (J Clin Invest, 2007, 117: 3786-3793). However, the molecular mechanisms by which lung injury triggers IL-1beta production, inflammation and fibrosis remain poorly understood. Based on the fact that cell/tissue injury and necrosis result in production of uric acid, we hypothesised that uric acid crystals formed at the injury site might represent a key danger signal activating the inflammasome to release IL-1beta thereby causing inflammatory lung pathologies. Methods: Mice deficient for MyD88, IL-1R1, NALP3, ASC or Casp-1 on C57Bl/6 genetic background were used. Uric acid concentration was determined in bronchoalveolar lavages and lung homogenates. Bleomycin sulfate (10mg/kg) in saline, uric acid or allopurinol crystals (5-50mg/kg) or saline alone were given through the airways by nasal instillation. The number of cells, chemokines, cytokines and TIMP-1 in the bronchoalveolar space and MPO activity in the lung were evaluated. MMP-2 and MMP-9 levels were determined by gelatin zymography. Results: Here we show that lung injury depends on the NALP3 inflammasome which is triggered by uric acid locally produced in the lung upon bleomycin-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase lead to a decrease in bleomycin-induced IL- 1beta production, lung inflammation, repair and fibrosis. Further, local administration of exogenous uric acid crystals recapitulates lung inflammation and repair which depend on the NALP3 inflammasome, MyD88 and IL-1R1 pathways, and TLR2 and TLR4 for optimal inflammation, but are independent of the IL-18 receptor. Conclusions: Uric acid released from injured cells constitutes a major endogenous danger signal which activates the NALP3 inflammasome leading to IL-1beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1beta production and chronic inflammatory lung pathology.
P Gasse; N Riteau; V Pétrilli; J Tschopp; V Lagente; V F J Quesniaux; B Ryffel; I Couillin
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Revue des maladies respiratoires     Volume:  25     ISSN:  0761-8425     ISO Abbreviation:  -     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-12-24     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8408032     Medline TA:  Rev Mal Respir     Country:  France    
Other Details:
Languages:  eng     Pagination:  1191     Citation Subset:  IM    
University of Orleans and CNRS, IEM-UMR6218, Orleans, France.
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