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

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.

Docosahexaenoic Acid Consumption Impedes Early Interferon- and Chemokine-Related Gene Expression While Suppressing Silica-Triggered Flaring of Murine Lupus

“…Consistent with our findings, cSiO 2 induced a type 1 IFN response in C57Bl/6 mice within 1 week of instillation (68). Moreover, cSiO 2 instillation induced accumulation of macrophages, neutrophils, and lymphocytes and marked expression of Ifnb, Irf7, and Ccl2 in the lungs of 129SV mice, whereas these responses were significantly reduced in corresponding interferon α/β receptor knockout mice (69).…”

“…The IFNα-producing capacity of pDCs obtained from lupus patients was enhanced following TLR stimulation and these responses correlated with disease activity and serum IFN-α (85). Importantly, cSiO 2 induced dsDNA release into the alveolar space in mice, and patients with silicosis had increased circulating dsDNA (68). RNA/DNA-containing immune complexes have been shown to elicit robust IFN-α production in pDCs (86)(87)(88)(89).…”

Hair follicle stem cell replication stress drives IFI16/STING-dependent inflammation in hidradenitis suppurativa

“…As reported for other pathological mechanisms, our results showed that cytosolic DNA of endogenous origin activates the STING pathway to induce type I IFN production in ORSCs. Indeed, excessive cGAS-STING-dependent type I IFN secretion has been involved in myocardial infarction (27) and in fibrotic interstitial lung disease (28). Genetic deficiencies that compromise DNA damage response functions also induce type I IFN and lead to autoinflammatory disease such as the immunodeficiency syndrome ataxia-telangiectasia due to mutations in the ATM gene (10).…”

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

“…During silicosis, silica can yield cytosolic dsDNA release and engage cGAS-STING, which activates DCs and macrophages to cause severe lung inflammation. It also leads to death of epithelial cells through the NLRP3 pathway and pulmonary fibrosis (193). Similarly, mtDNA release in renal tubule cells has been found to be associated with acute kidney injury by cytotoxic drugs and chronic renal fibrosis (194,195).…”