ArticleArthritis & rheumatology (Hoboken, N.J.)2020
Bioactive Plasma Mitochondrial DNA Is Associated With Disease Progression in Scleroderma-Associated Interstitial Lung Disease.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 53 citations in OpenAlex.
- Identifying therapeutic target genes for rheumatoid arthritis-associated interstitial lung disease by systematic druggable genome-wide Mendelian randomization analysis.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Anifrolumab-A Potential New Systemic Sclerosis Treatment.Journal of clinical medicine · 2026Review
- The cGAS-STING pathway in fibroblast microenvironment: from molecular mechanisms to targeted therapies.Apoptosis : an international journal on programmed cell death · 2026Review
- Molecular Mechanisms of cGAS-STING Axis and Mitochondrial Dysfunction-Related Diseases in Humans: A Comprehensive Review.Current neuropharmacology · 2026Review
- Associations with, and predictors of, progression in systemic sclerosis-related interstitial lung disease: a scoping literature review.European respiratory review : an official journal of the European Respiratory Society · 2026Article
- Cyclic GMP-AMP synthase expression is enhanced in systemic sclerosis-associated interstitial lung disease and stimulates inflammatory myofibroblast activation.The European respiratory journal · 2025Article
- Pathogenesis of systemic sclerosis: an integrative review of recent advances.Journal of rheumatic diseases · 2025Review
- Serum Proteomic Markers in Patients with Systemic Sclerosis in Relation to Silica Exposure.Journal of clinical medicine · 2025Article
- Role of toll-like receptors in pulmonary immunity: mechanisms and therapeutic implications.Frontiers in immunology · 2025Review
- Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.American journal of respiratory and critical care medicine · 2025Article
- Cell-free mitochondrial DNA as a pro-inflammatory agent in blood circulation: mechanisms, therapeutic implications, and clinical challenges in immune dysregulation.Frontiers in immunology · 2025Review
- Cell-free DNA: a metabolic byproduct with diagnostic and prognostic potential in rheumatic disorders.Frontiers in pharmacology · 2025Review
- Article
- Emerging therapeutic targets in systemic sclerosis.Journal of molecular medicine (Berlin, Germany) · 2024Review
- Systemic sclerosis interstitial lung disease: unmet needs and potential solutions.Nature reviews. Rheumatology · 2024Review
- Mitochondrial DNA Sensing Pathogen Recognition Receptors in Systemic Sclerosis Associated Interstitial Lung Disease: A Review.Current treatment options in rheumatology · 2023Article
- Platelet-Derived Microparticles and Autoimmune Diseases.International journal of molecular sciences · 2023Review
- Current Concepts on the Pathogenesis of Systemic Sclerosis.Clinical reviews in allergy & immunology · 2023Review
- Protein engineering reveals that gasdermin A preferentially targets mitochondrial membranes over the plasma membrane during pyroptosis.The Journal of biological chemistry · 2023Article
- Proteomics: Potential techniques for discovering the pathogenesis of connective tissue diseases-interstitial lung disease.Frontiers in immunology · 2023Review
Corrections and comments
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Authors and funding
22 authors at 2 institutions in 1 country.
Funding
Abstract
objectiveSystemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterized by variable clinical outcomes, activation of innate immune pattern-recognition receptors (PRRs), and accumulation of α-smooth muscle actin (α-SMA)-expressing myofibroblasts. The aim of this study was to identify an association between these entities and mitochondrial DNA (mtDNA), an endogenous ligand for the intracellular DNA-sensing PRRs Toll-like receptor 9 (TLR-9) and cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING), which has yet to be determined.
methodsHuman lung fibroblasts (HLFs) from normal donors and SSc-ILD explants were treated with synthetic CpG DNA and assayed for α-SMA expression and extracellular mtDNA using quantitative polymerase chain reaction for the human MT-ATP6 gene. Plasma MT-ATP6 concentrations were evaluated in 2 independent SSc-ILD cohorts and demographically matched controls. The ability of SSc-ILD and control plasma to induce TLR-9 and cGAS/STING activation was evaluated with commercially available HEK 293 reporter cells. Plasma concentrations of type I interferons (IFNs), interleukin-6 (IL-6), and oxidized DNA were measured using electrochemiluminescence and enzyme-linked immunosorbent assay-based methods. Extracellular vesicles (EVs) precipitated from plasma were evaluated for MT-ATP6 concentrations and proteomics via liquid chromatography mass spectrometry.
resultsNormal HLFs and SSc-ILD fibroblasts developed increased α-SMA expression and MT-ATP6 release following CpG stimulation. Plasma mtDNA concentrations were increased in the 2 SSc-ILD cohorts, reflective of ventilatory decline, and were positively associated with both TLR-9 and cGAS/STING activation as well as type I IFN and IL-6 expression. Plasma mtDNA was not oxidized and was conveyed by EVs displaying a proteomics profile consistent with a multicellular origin.
conclusionThese findings demonstrate a previously unrecognized connection between EV-encapsulated mtDNA, clinical outcomes, and intracellular DNA-sensing PRR activation in SSc-ILD. Further study of these interactions could catalyze novel mechanistic and therapeutic insights into SSc-ILD and related disorders.
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