Inhalation of silica crystals causes inflammation in the alveolar space. Prolonged exposure to silica can lead to the development of silicosis, an irreversible, fibrotic pulmonary disease. The mechanisms by which silica and other crystals activate immune cells are not well understood. Here we demonstrate that silica and aluminum salt crystals activated inflammasomes formed by the cytoplasmic receptor NALP3. NALP3 activation required phagocytosis of crystals, and this uptake subsequently led to lysosomal damage and rupture. 'Sterile' lysosomal damage (without crystals) also induced NALP3 activation, and inhibition of either phagosomal acidification or cathepsin B activity impaired NALP3 activation. Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal.
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MyD88-deficient and TRIF-deficient mice were provided by S. Akira (Osaka University). We thank A. Cerny and Joseph Boulanger for animal husbandry and genotyping; D. Kalvakolanu (University of Maryland School of Medicine) for providing J2 recombinant retroviruses; and J. Lee and H. Kornfeld for help with the lung inflammation model. Supported by the Deutsche Forschungsgemeinschaft (Ho2783/2-1 to V.H. and GK1202 to F.B.) and the US National Institutes of Health (R01 AI-065483 to E.L., RO1 AI-067497 to K.A.F. and RO1 AI043543 to K.L.R.).
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Hornung, V., Bauernfeind, F., Halle, A. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9, 847–856 (2008). https://doi.org/10.1038/ni.1631
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