STING-dependent sensing of self-DNA drives silica-induced lung inflammation

Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. In mice, silica induces lung cell death and self-dsDNA release in the bronchoalveolar space that activates STING pathway. Degradation of...

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Bibliographic Details
Published in:	Nature communications 2018-12, Vol.9 (1), p.5226-19, Article 5226
Main Authors:	Benmerzoug, Sulayman, Rose, Stéphanie, Bounab, Badreddine, Gosset, David, Duneau, Laure, Chenuet, Pauline, Mollet, Lucile, Le Bert, Marc, Lambers, Christopher, Geleff, Silvana, Roth, Michael, Fauconnier, Louis, Sedda, Delphine, Carvalho, Clarisse, Perche, Olivier, Laurenceau, David, Ryffel, Bernhard, Apetoh, Lionel, Kiziltunc, Ahmet, Uslu, Hakan, Albez, Fadime Sultan, Akgun, Metin, Togbe, Dieudonnée, Quesniaux, Valerie F J
Format:	Article
Language:	eng
Subjects:	Activation Alveoli Animals Bronchus Cell death Cells, Cultured Chemokine CXCL10 - metabolism CXCL10 protein Dendritic cells Dendritic Cells - metabolism Deoxyribonuclease Deoxyribonucleic acid DNA DNA - genetics DNA - metabolism Exposure Fibrosis Human health and pathology Humans Infectious diseases Inflammation Interferon Life Sciences Lung diseases Macrophages Macrophages - metabolism Membrane Proteins - genetics Membrane Proteins - metabolism Mice, Inbred C57BL Mice, Knockout Mitochondria Patients Pneumonia - genetics Pneumonia - metabolism Silica Silicon dioxide Silicon Dioxide - chemistry Silicon Dioxide - metabolism Silicosis Silicosis - metabolism Sputum Sputum - metabolism Stimulators
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Summary:	Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. In mice, silica induces lung cell death and self-dsDNA release in the bronchoalveolar space that activates STING pathway. Degradation of extracellular self-dsDNA by DNase I inhibits silica-induced STING activation and the downstream type I IFN response. Patients with silicosis have increased circulating dsDNA and CXCL10 in sputum, and patients with fibrotic interstitial lung disease display STING activation and CXCL10 in the lung. In vitro, while mitochondrial dsDNA is sensed by cGAS-STING in dendritic cells, in macrophages extracellular dsDNA activates STING independent of cGAS after silica exposure. These results reveal an essential function of STING-mediated self-dsDNA sensing after silica exposure, and identify DNase I as a potential therapy for silica-induced lung inflammation.
ISSN:	2041-1723 2041-1723