ArticleScience translational medicine2018
Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8.
Article in Science translational medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 142 papers.
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Who cites it
142 citing papers in PubMed, 234 citations in OpenAlex.
- Interferon-Mediated Regulation of Memory B Cell Identity and Function.Immunological reviews · 2026Review
- Reactive oxygen species and metabolic checkpoints shape plasmacytoid dendritic cell fate in infection and autoimmunity.Redox biology · 2026Review
- A symposium update on the key perspectives in systemic sclerosis and systemic lupus erythematosus.Journal of translational autoimmunity · 2026Review
- Tetrameric assembly disruption impairs CXCL4 chaperon ability for DNA and type I interferon immune amplification.Communications biology · 2026Article
- Age- and tissue-dependent diversity of human plasmacytoid dendritic cells uncovers a cycling subset dominant in early life and cancer.Immunity · 2026Article
- Fibrosis-memory is mediated by IL-3-producing T cells and drives progression of fibrosis.The Journal of clinical investigation · 2026Article
- CXCL4 and CXCL4L1 activate human macrophage via TLR4 signaling to modulate inflammatory responses.Cell insight · 2026Article
- Knowledge gaps and research priorities to understand sex differences in immunity.PLoS biology · 2026Review
- Skin Biopsies Enhance Prediction of Clinical Trajectory in Diffuse Cutaneous Systemic Sclerosis.Arthritis & rheumatology (Hoboken, N.J.) · 2026Article
- Anifrolumab-A Potential New Systemic Sclerosis Treatment.Journal of clinical medicine · 2026Review
- Plasmacytoid dendritic cells in systemic and cutaneous lupus erythematosus: an evolving understanding.Frontiers in immunology · 2026Review
- TLR7 signaling aggravates lung inflammation associated with increased anti-Scl-70 autoantibody production in murine bleomycin-induced systemic sclerosis.Frontiers in immunology · 2026Article
- Escape From X Chromosome Inactivation as a Driver of Plasmacytoid DC Heterogeneity in Health and Disease.Immunological reviews · 2025Review
- EGFR-STAT1 pathway drives fibrosis initiation in fibroinflammatory skin diseases.Nature communications · 2025Article
- The Immune Microenvironment: New Therapeutic Implications in Organ Fibrosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Agonists and Antagonists Show Different Unbinding Paths from the TLR8 Receptor.Journal of chemical information and modeling · 2025Article
- Dendritic cell heterogeneity and its role in connective tissue diseases.Inflammation and regeneration · 2025Review
- Sex Bias in Systemic Sclerosis: from Clinical to Immunological Differences.Clinical reviews in allergy & immunology · 2025Review
- The Inactive X Chromosome: A Genetic Driver of Female-Biased Rheumatic Autoimmune Disorders?European journal of immunology · 2025Review
- Long noncoding RNA PARAL1 regulates myeloid dendritic cell differentiation and TLR signaling.Genes and immunity · 2025Article
82 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Systemic sclerosis (SSc) is a multisystem life-threatening fibrosing disorder that lacks effective treatment. The link between the inflammation observed in organs such as the skin and profibrotic mechanisms is not well understood. The plasmacytoid dendritic cell (pDC) is a key cell type mediating Toll-like receptor (TLR)-induced inflammation in autoimmune disease patients, including lupus and skin diseases with interface dermatitis. However, the role of pDCs in fibrosis is less clear. We show that pDCs infiltrate the skin of SSc patients and are chronically activated, leading to secretion of interferon-α (IFN-α) and CXCL4, which are both hallmarks of the disease. We demonstrate that the secretion of CXCL4 is under the control of phosphatidylinositol 3-kinase δ and is due to the aberrant presence of TLR8 on pDCs of SSc patients, which is not seen in healthy donors or in lupus pDCs, and that CXCL4 primarily acts by potentiating TLR8- but also TLR9-induced IFN production by pDCs. Depleting pDCs prevented disease in a mouse model of scleroderma and could revert fibrosis in mice with established disease. In contrast, the disease was exacerbated in mice transgenic for TLR8 with recruitment of pDCs to the fibrotic skin, whereas TLR7 only partially contributed to the inflammatory response, indicating that TLR8 is the key RNA-sensing TLR involved in the establishment of fibrosis. We conclude that the pDC is an essential cell type involved in the pathogenesis of SSc and its removal using depleting antibodies or attenuating pDC function could be a novel approach to treat SSc patients.
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Registered trials
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.