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070 - Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis - 05/12/08

Doi : RMR-11-2008-25-9-0761-8425-101019-200810935 

P. Gasse [1],

N. Riteau [1],

V. Pétrilli [2],

J. Tschopp [2],

V. Lagente [3],

V.F.J. Quesniaux [1],

B. Ryffel [1],

I. Couillin [1 et 4]

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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-1β 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-1β 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- 1β 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-1β production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1β production and chronic inflammatory lung pathology.




© 2008 Elsevier Masson SAS. Tous droits réservés.
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Vol 25 - N° 9

P. 1191 - novembre 2008 Retour au numéro
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