Article abstract
Nature Immunology 9, 847 - 856 (2008)
Published online: 11 July 2008 | doi:10.1038/ni.1631
Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization
Veit Hornung1,5, Franz Bauernfeind2,5, Annett Halle1, Eivind O Samstad1,3, Hajime Kono4, Kenneth L Rock4, Katherine A Fitzgerald1 & Eicke Latz1,3
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.
- Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
- Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilians University of Munich 80336, Germany.
- Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
- These authors contributed equally to this work.
Correspondence to: Eicke Latz1,3 e-mail: eicke.latz@umassmed.edu
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