ArticleThe American journal of pathology2013
Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma.
Article in The American journal of pathology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 152 papers, 3 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
152 citing papers in PubMed, 3 syntheses or guidelines pooled it, 257 citations in OpenAlex.
- Unfolding the pathogenesis of scleroderma through genomics and epigenomics.Journal of autoimmunity · 2017Pooled it
- A systematic review of overlapping microRNA patterns in systemic sclerosis and idiopathic pulmonary fibrosis.European respiratory review : an official journal of the European Respiratory Society · 2017Pooled it
- Pooled it
- Trial
- Programmed death-ligand 1 on ex vivo-expanded toll-like-receptor-Bregs prevents allograft rejection by Breg viability promotion, CD4American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2026Article
- Self-oxidatively crosslinked sprayable hydrogel for microenvironment remodeling and accelerated healing of recurrent aphthous ulcers.Materials today. Bio · 2026Article
- Pharmabiotics, Phocaeicola dorei, ameliorates cholestatic liver fibrosis by alleviating macrophage efferocytosis of neutrophils.Nature communications · 2026Article
- Epidermal PPARγ Signaling as a Suppressor of Toll-like Receptor-Mediated Inflammation and Fibrosis: Relevance to Cutaneous Squamous Cell Carcinoma.International journal of molecular sciences · 2026Article
- Collagen-Enriched Immunomodulatory Hydrogel for Tendon Regeneration.Gels (Basel, Switzerland) · 2026Article
- LncRNA RMST knockout inhibits fibrosis by down-regulating Smad3 during mouse skin wound healing.Biochemistry and biophysics reports · 2026Article
- Review
- The "Mechano-Metabolic-Immune" crosstalk within the skeletal muscle microenvironment: evolution of homeostatic remodeling and quality control mechanisms.Frontiers in immunology · 2026Review
- Multi-omics integration and machine learning reveal gut-immune signatures in idiopathic pulmonary fibrosis: insights from bulk RNA-seq, single-cell profiles, spatial transcriptomics, and experimental validation.Frontiers in immunology · 2026Article
- Protocatechuic acid and syringin improve cardiac damage and autonomic imbalance caused by dyslipidemia in mice.Frontiers in pharmacology · 2026Article
- Lyn expression in macrophages promotes TLR activation and restricts proliferation in an isoform-independent manner.Journal of leukocyte biology · 2025Article
- Article
- Article
- Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis.eLife · 2025Article
- The multi-faceted immune modulatory role of S100A4 in cancer and chronic inflammatory disease.Frontiers in immunology · 2025Review
- Glutamate enhances the production of inflammatory cytokines IL-6 and IL-11, as well as chemokines CXCL2, CXCL3, and CXCL8 in keloid fibroblasts.Frontiers in molecular biosciences · 2025Article
92 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
Because recent studies implicate Toll-like receptors (TLRs) in the pathogenesis of fibrosis, we sought to investigate the in vitro and in vivo role and mechanism of TLR4-mediated fibroblast responses in fibrogenesis. We found that TLR4 was constitutively expressed, and accumulation of endogenous TLR4 ligands significantly elevated, in lesional skin and lung tissues from patients with scleroderma. Activation of TLR4 signaling in explanted fibroblasts resulted in enhanced collagen synthesis and increased expression of multiple genes involved in tissue remodeling and extracellular matrix homeostasis. Moreover, TLR4 dramatically enhanced the sensitivity of fibroblasts to the stimulatory effect of transforming growth factor-β1. These profibrotic responses were abrogated by both genetic and pharmacological disruption of TLR4 signaling in vitro, and skin fibrosis induced by bleomycin in vivo was attenuated in mice harboring a mutated TLR4. Activation of TLR4 in fibroblasts augmented the intensity of canonical Smad signaling, and was accompanied by suppression of anti-fibrotic microRNA expression. Together, these results suggest a novel model to account for persistent fibrogenesis in scleroderma, in which activation of fibroblast TLR4 signaling, triggered by damage-associated endogenous TLR4 ligands, results in augmented transforming growth factor-β1 sensitivity with increased matrix production and progressive connective tissue remodeling. Under these conditions, fibroblast TLR4 serves as the switch for converting self-limited tissue repair into intractable fibrosis.
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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.