title: The Nalp3 inflammasome is essential for the development of silicosis.
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)-1beta 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.
authors.affiliation: Division of Allergy and Immunology, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Cassel
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.forename: Shankar S
authors.initials: SS
authors.lastname: Iyer
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Sadler
authors.forename: Oscar R
authors.initials: OR
authors.lastname: Colegio
authors.forename: Linda A
authors.initials: LA
authors.lastname: Tephly
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rothman
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001194:Asbestos / Q000008:administration & dosage / Q000494:pharmacology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000494:pharmacology; D012829:Silicosis / Q000276:immunology* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D001194:Asbestos; D012822:Silicon Dioxide; D003094:Collagen; D011188:Potassium