Article

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

  • Nature Immunology volume 9, pages 847856 (2008)
  • doi:10.1038/ni.1631
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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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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.).

Author information

Author notes

    • Veit Hornung
    •  & Franz Bauernfeind

    These authors contributed equally to this work.

Affiliations

  1. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

    • Veit Hornung
    • , Annett Halle
    • , Eivind O Samstad
    • , Katherine A Fitzgerald
    •  & Eicke Latz
  2. Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilians University of Munich 80336, Germany.

    • Franz Bauernfeind
  3. Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.

    • Eivind O Samstad
    •  & Eicke Latz
  4. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

    • Hajime Kono
    •  & Kenneth L Rock

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Corresponding author

Correspondence to Eicke Latz.

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