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

Sulayman Benmerzoug,Stéphanie Rose,Fadime Sultan Albez,Badreddine Bounab,Marc Le Bert,Delphine Sedda,Silvana Geleff,Christopher Lambers,Lucile Mollet,Bernhard Ryffel,Lionel Apétoh ,Michael Roth,Hakan Uslu,Metin Akgün ,David Gosset,Dieudonnée Togbé ,Louis Fauconnier,David Laurenceau,Laure Duneau,Pauline Chenuet,Olivier Perche,Ahmet Kızıltunç ,Clarisse Carvalho,Valérie Quesniaux

doi:10.1038/s41467-018-07425-1

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.

Highlights

Silica particles induce lung inflammation and fibrosis
Release in the bronchoalveolar space (Fig. 1a). This was accompanied by the overexpression of stimulator of interferon genes (STING) (Tmem173) and cyclic GMP–AMP synthase (cGAS)
T Pulmonary IFN-αβ and CXCL10. u Neutrophils, macrophages, and protein extravasation in the BALF. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 (Kruskal–Wallis test followed by Dunn post test)

Summary

Introduction

Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. 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. 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. We hypothesized that airway silica exposure induced cell death, release of self-DNA, and triggered the stimulator of interferon genes (STING) pathway. Mouse airway exposure to silica microparticles induces cell death, self-dsDNA leakage, and inflammatory response through STING-dependent type 1 IFN signaling and downstream CXCL10 expression

Methods

Results

Conclusion