The Nalp3 inflammasome is essential for the development of silicosis

Suzanne L. Cassel, Stephanie C. Eisenbarth, Shankar S. Iyer, Jeffrey J. Sadler, Oscar R. Colegio, Linda A. Tephly, A. Brent Carter, Paul B. Rothman, Richard A. Flavell, Fayyaz S. Sutterwala

Research output: Contribution to journalArticlepeer-review

Abstract

Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1β and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis.

Original languageEnglish (US)
Pages (from-to)9035-9040
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number26
DOIs
StatePublished - Jul 1 2008
Externally publishedYes

Keywords

  • Asbestosis
  • Caspase-1
  • Interleukin-1β
  • NLRP3

ASJC Scopus subject areas

  • General

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