ArticleArthritis & rheumatology (Hoboken, N.J.)2016
Toll-like Receptor 9 Signaling Is Augmented in Systemic Sclerosis and Elicits Transforming Growth Factor β-Dependent Fibroblast Activation.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 37 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
37 citing papers in PubMed, 66 citations in OpenAlex.
- Cyclic GMP-AMP synthase expression is enhanced in systemic sclerosis-associated interstitial lung disease and stimulates inflammatory myofibroblast activation.The European respiratory journal · 2025Article
- Geographic Clustering of Systemic Sclerosis in Areas of Environmental Pollution.Arthritis care & research · 2025Article
- CD103+ dendritic cell-fibroblast crosstalk via TLR9, TDO2, and AHR signaling drives lung fibrogenesis.JCI insight · 2025Article
- Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.American journal of respiratory and critical care medicine · 2025Article
- Profiling of Toll-like Receptors and Related Signaling Mediators in the Pathogenesis of Morphea.Dermatology practical & conceptual · 2024Article
- TLR9 activation in large wound induces tissue repair and hair follicle regeneration via γδT cells.Cell death & disease · 2024Article
- Anti-Th/To Antibodies in Scleroderma: Good Prognosis or Serious Concern?Journal of clinical medicine · 2024Review
- Mitochondrial DNA Sensing Pathogen Recognition Receptors in Systemic Sclerosis Associated Interstitial Lung Disease: A Review.Current treatment options in rheumatology · 2023Article
- Fibronectin-EDA accumulates via reduced ubiquitination downstream of Toll-like receptor 9 activation in SSc-ILD fibroblasts.American journal of physiology. Lung cellular and molecular physiology · 2022Article
- Anemia Is an Indicator for Worse Organ Damage Trajectories in Patients with Systemic Sclerosis: A Retrospective Study.Journal of clinical medicine · 2022Article
- Diffuse cutaneous systemic sclerosis following SARS-Co V-2 vaccination.Journal of autoimmunity · 2022Review
- 17,20S(OH)International journal of molecular sciences · 2021Article
- Idiopathic pulmonary fibrosis and systemic sclerosis: pathogenic mechanisms and therapeutic interventions.Cellular and molecular life sciences : CMLS · 2021Review
- Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis.Cellular and molecular life sciences : CMLS · 2021Review
- Innate Immune Modulation Induced by EBV Lytic Infection Promotes Endothelial Cell Inflammation and Vascular Injury in Scleroderma.Frontiers in immunology · 2021Observational
- Innate immune response in systemic autoimmune diseases: a potential target of therapy.Inflammopharmacology · 2020Review
- Bioactive Plasma Mitochondrial DNA Is Associated With Disease Progression in Scleroderma-Associated Interstitial Lung Disease.Arthritis & rheumatology (Hoboken, N.J.) · 2020Article
- Toll-like receptors in mediating pathogenesis in systemic sclerosis.Clinical and experimental immunology · 2020Review
- Mitochondria, Aging, and Cellular Senescence: Implications for Scleroderma.Current rheumatology reports · 2020Review
- Mitochondrial quality control in pulmonary fibrosis.Redox biology · 2020Review
Corrections and comments
- Erratum issued
Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
objectiveAlthough transforming growth factor β (TGFβ) is recognized as being a key trigger of fibroblast activation in systemic sclerosis (SSc), prominent innate immunity suggests that additional pathways contribute to disease persistence. Toll-like receptor 9 (TLR9) is implicated in autoimmunity and fibrosis; however, the expression, mechanism of action, and pathogenic role of TLR9 signaling in SSc remain uncharacterized. The aim of this study was to explore the expression, activity, and potential pathogenic role of TLR9 in the context of skin fibrosis in SSc and in mouse models of experimental fibrosis.
methodsExpression and localization of TLR9 were evaluated in SSc skin biopsy specimens and explanted skin fibroblasts. Fibrotic responses elicited by type A CpG oligonucleotide and mitochondrial DNA (mtDNA) were examined in human skin fibroblasts by a combination of real-time quantitative polymerase chain reaction, Western blot analysis, transient transfection, immunofluorescence microscopy, and functional assays. Expression of TLR9 was examined in 2 distinct mouse models of experimental fibrosis.
resultsSkin biopsy specimens obtained from 2 independent cohorts of SSc patients showed up-regulation of TLR9, and myofibroblasts were the major cellular source. Moreover, SSc skin biopsy specimens showed evidence of TLR9 pathway activation. CpG induced robust TLR9-dependent fibrotic responses in explanted normal fibroblasts that could be blocked by bortezomib and were mediated through the action of endogenous TGFβ. Mice with experimental fibrosis showed a time-dependent increase in TLR9 localized primarily to myofibroblasts in the dermis.
conclusionIn isolated fibroblasts, TLR9 elicits fibrotic responses mediated via endogenous TGFβ. In patients with SSc, mtDNA and other damage-associated TLR9 ligands in the skin might trigger localized activation of TLR9 signaling, TGFβ production, and consequent fibroblast activation. Disrupting this fibrotic process with inhibitors targeting TLR9 or its downstream signaling pathways might therefore represent a novel approach to SSc therapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.