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

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

Nature communications (2018-12-13)
Sulayman Benmerzoug, Stéphanie Rose, Badreddine Bounab, David Gosset, Laure Duneau, Pauline Chenuet, Lucile Mollet, Marc Le Bert, Christopher Lambers, Silvana Geleff, Michael Roth, Louis Fauconnier, Delphine Sedda, Clarisse Carvalho, Olivier Perche, David Laurenceau, Bernhard Ryffel, Lionel Apetoh, Ahmet Kiziltunc, Hakan Uslu, Fadime Sultan Albez, Metin Akgun, Dieudonnée Togbe, Valerie F J Quesniaux
PMID30523277
ABSTRACT

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.