Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica
Abstract
The inhalation of airborne pollutants, such as asbestos or silica, is linked to inflammation of the lung, fibrosis, and lung cancer. How the presence of pathogenic dust is recognized and how chronic inflammatory diseases are triggered are poorly understood. Here, we show that asbestos and silica are sensed by the Nalp3 inflammasome, whose subsequent activation leads to interleukin-1β secretion. Inflammasome activation is triggered by reactive oxygen species, which are generated by a NADPH oxidase upon particle phagocytosis. (NADPH is the reduced form of nicotinamide adenine dinucleotide phosphate.) In a model of asbestos inhalation, Nalp3–/– mice showed diminished recruitment of inflammatory cells to the lungs, paralleled by lower cytokine production. Our findings implicate the Nalp3 inflammasome in particulate matter–related pulmonary diseases and support its role as a major proinflammatory “danger” receptor.
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We thank T. Barrett and M. MacPherson for technical assistance with animal experiments; K. Butnor for pathology analysis; M. MacPherson, V. Alexeeva, and M. von Turkovich for performing SEM analyses; E. Logette, D. Muruve, and F. Martinon for helpful discussions; P. Vandenabeele, University of Ghent, for the antibody against caspase1; and V. Dixit (Genentech, San Francisco) for the ASC–/– and Ipaf–/– mice. This work was supported by a NIH Program Project grant from the National Heart Lung and Blood Institute (P01HL67004) to B.T.M. and a grant for work in molecular oncology from the Commission for Technology and Innovation, National Centers of Competence in Research (CTI, NCCR), Switzerland, to J.T. and a MUGEN grant to J.T. C.D. is supported by an EMBO long-term fellowship, V.P. is supported by a Marie Curie Intra-European Fellowship.
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Science
Volume 320 | Issue 5876
2 May 2008
2 May 2008
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American Association for the Advancement of Science.
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Received: 26 February 2008
Accepted: 25 March 2008
Published in print: 2 May 2008
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