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

Nat Immunol 2008 Aug 11;9(8):847-56. Epub 2008 Jul 11.

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

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/ni.1631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834784PMC
August 2008
8 Reads

Publication Analysis

Top Keywords

nalp3 activation
12
lysosomal damage
12
silica crystals
12
nalp3 inflammasome
8
nalp3
6
silica
5
crystals
5
nalp3 nalp3
4
receptor nalp3
4
activation required
4
uptake subsequently
4
crystals uptake
4
phagocytosis crystals
4
required phagocytosis
4
cytoplasmic receptor
4
activated inflammasomes
4
understood demonstrate
4
well understood
4
cells well
4
immune cells
4

References

(Supplied by CrossRef)

BT Mossman et al.
Am. J. Respir. Crit. Care Med. 1998

F Huaux et al.
Curr. Opin. Allergy Clin. Immunol. 2007

F Martinon et al.
Nature 2006

V Petrilli et al.
Curr. Opin. Immunol. 2007

L Agostini et al.
Immunity 2004

CA Dinarello et al.
Ann. NY Acad. Sci. 1998

DA Muruve et al.
Nature 2008

A Ozinsky et al.
Proc. Natl. Acad. Sci. USA 2000

GD Brown et al.
J. Exp. Med. 2002

S Mariathasan et al.
Nature 2006

S Mariathasan et al.
Nature 2004

Similar Publications