Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization

Abstract

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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Figure 1: Silica induction of the release of mature IL–1β and activated caspase-1 by human PBMCs is caspase-1 dependent.
Figure 2: Silica-mediated neutrophil influx in a model of acute lung inflammation is mediated by IL-1.
Figure 3: Silica-mediated release of matured IL-1β and activated caspase-1 is mediated by the NALP3 inflammasome.
Figure 4: Inflammasome activation requires phagosomal uptake of crystals but is independent of the phagosomal reactive oxygen species system.
Figure 5: Phagocytosis of crystals leads to lysosomal destabilization.
Figure 6: Silica-mediated IL-1β production is partially dependent on cathepsin B.
Figure 7: Alum activates the NALP3 inflammasome through lysosomal destabilization.
Figure 8: Rupture of 'sterile' lysosomes activates the NALP3 inflammasome.

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Acknowledgements

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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Correspondence to Eicke Latz.

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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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