STING-dependent sensing of self-DNA drives silica-induced lung inflammation.
Sulayman BenmerzougStéphanie RoseBadreddine BounabDavid GossetLaure DuneauPauline ChenuetLucile MolletMarc Le BertChristopher LambersSilvana GeleffMichael RothLouis FauconnierDelphine SeddaClarisse CarvalhoOlivier PercheDavid LaurenceauBernhard RyffelLionel ApetohAhmet KiziltuncHakan UsluFadime Sultan AlbezMetin AkgunDieudonnée TogbeValerie F J QuesniauxPublished in: Nature communications (2018)
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.
Keyphrases
- oxidative stress
- dendritic cells
- diabetic rats
- high glucose
- cell death
- interstitial lung disease
- systemic sclerosis
- drug induced
- immune response
- genome wide
- mycobacterium tuberculosis
- rheumatoid arthritis
- metabolic syndrome
- single cell
- adipose tissue
- transcription factor
- circulating tumor
- liver fibrosis
- circulating tumor cells
- cell cycle arrest
- innate immune