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The aim of this study was to identify an association between these entities and mitochondrial DNA (mtDNA), an endogenous ligand for the intracellular DNA\u2013sensing PRRs Toll\u2010like receptor 9 (TLR\u20109) and cyclic GMP\u2010AMP synthase\/stimulator of interferon genes (cGAS\/STING), which has yet to be determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human lung fibroblasts (HLFs) from normal donors and SSc\u2010ILD explants were treated with synthetic CpG DNA and assayed for \u03b1\u2010SMA expression and extracellular mtDNA using quantitative polymerase chain reaction for the human MT\u2010ATP6 gene. Plasma MT\u2010ATP6 concentrations were evaluated in 2 independent SSc\u2010ILD cohorts and demographically matched controls. The ability of SSc\u2010ILD and control plasma to induce TLR\u20109 and cGAS\/STING activation was evaluated with commercially available HEK 293 reporter cells. Plasma concentrations of type I interferons (IFNs), interleukin\u20106 (IL\u20106), and oxidized DNA were measured using electrochemiluminescence and enzyme\u2010linked immunosorbent assay\u2013based methods. Extracellular vesicles (EVs) precipitated from plasma were evaluated for MT\u2010ATP6 concentrations and proteomics via liquid chromatography mass spectrometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Normal HLFs and SSc\u2010ILD fibroblasts developed increased \u03b1\u2010SMA expression and MT\u2010ATP6 release following CpG stimulation. Plasma mtDNA concentrations were increased in the 2 SSc\u2010ILD cohorts, reflective of ventilatory decline, and were positively associated with both TLR\u20109 and cGAS\/STING activation as well as type I IFN and IL\u20106 expression. Plasma mtDNA was not oxidized and was conveyed by EVs displaying a proteomics profile consistent with a multicellular origin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings demonstrate a previously unrecognized connection between EV\u2010encapsulated mtDNA, clinical outcomes, and intracellular DNA\u2013sensing PRR activation in SSc\u2010ILD. Further study of these interactions could catalyze novel mechanistic and therapeutic insights into SSc\u2010ILD and related disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41418","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T03:21:41Z","timestamp":1593487301000},"page":"1905-1915","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Bioactive Plasma Mitochondrial DNA Is Associated With Disease Progression in Scleroderma\u2010Associated Interstitial Lung Disease"],"prefix":"10.1002","volume":"72","author":[{"given":"Changwan","family":"Ryu","sequence":"first","affiliation":[{"name":"Yale University School of Medicine  New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali","family":"Walia","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine  New Haven 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