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.

Details

Title
STING-dependent sensing of self-DNA drives silica-induced lung inflammation
Author
Benmerzoug, Sulayman 1 ; Rose, Stéphanie 1 ; Bounab, Badreddine 1 ; Gosset, David 2 ; Duneau, Laure 1 ; Chenuet, Pauline 3 ; Mollet, Lucile 2 ; Marc Le Bert 1   VIAFID ORCID Logo  ; Lambers, Christopher 4 ; Geleff, Silvana 5 ; Roth, Michael 6   VIAFID ORCID Logo  ; Fauconnier, Louis 3 ; Sedda, Delphine 1 ; Carvalho, Clarisse 1 ; Perche, Olivier 7 ; Laurenceau, David 7 ; Ryffel, Bernhard 1 ; Apetoh, Lionel 8   VIAFID ORCID Logo  ; Kiziltunc, Ahmet 9 ; Uslu, Hakan 10 ; Fadime Sultan Albez 11 ; Akgun, Metin 11 ; Togbe, Dieudonnée 3 ; Quesniaux, Valerie F J 1   VIAFID ORCID Logo 

1  CNRS, UMR7355, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orleans, France 
2  Center for Molecular Biophysics, CNRS UPR4301, Orleans, France 
3  Artimmune SAS, rue Buffon, Orleans, France 
4  Department of Thoracic Surgery, Lung Transplantation Program, Vienna, Austria 
5  Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 
6  Pulmonary Cell Research & Pneumology, Department Biomedicine, University& University Hospital Basel, Basel, Switzerland 
7  CNRS, UMR7355, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orleans, France; Genetics Department, Regional Hospital Orleans, Orleans, France 
8  INSERM, U1231, Dijon, France 
9  Department of Biochemistry, Atatürk University School of Medicine, Erzurum, Turkey 
10  Department of Clinical Microbiology, Atatürk University School of Medicine, Erzurum, Turkey 
11  Department of Pulmonary Medicine, Atatürk University School of Medicine, Erzurum, Turkey 
Pages
1-19
Publication year
2018
Publication date
Dec 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-07425-1
ProQuest document ID
2151204143
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.