Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization.
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.
Hornung
Veit
V
Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Bauernfeind
Franz
F
Halle
Annett
A
Samstad
Eivind O
EO
Kono
Hajime
H
Rock
Kenneth L
KL
Fitzgerald
Katherine A
KA
Latz
Eicke
E
D017607:Aluminum Compounds / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012822:Silicon Dioxide / Q000378:metabolism; D012829:Silicosis / Q000276:immunology* / Q000473:pathology*
D017607:Aluminum Compounds; D002352:Carrier Proteins; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012822:Silicon Dioxide