Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization
Department of Medicine, Division of Infectious Diseases and Immunology; Department of Pathology
Aluminum Compounds; Animals; Carrier Proteins; Inflammation; Inflammation Mediators; Macrophages; Mice; Mice, Inbred C57BL; Silicon Dioxide; Silicosis
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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Citation: Nat Immunol. 2008 Aug;9(8):847-56. Epub 2008 Jul 11. Link to article on publisher's site