ArticleJCI insight2018
TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung.
Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 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
82 citing papers in PubMed, 130 citations in OpenAlex.
- Physical continuity at biomaterial-ECM interfaces is associated with reduced fibroblast activation and NF-κB signaling.Biomaterials · 2026Article
- MAP Crosslinker Chirality Regulates Macrophage Polarization Through MD-2 Engagement and Enables Tunable Immunomodulation Through Novel Peptide Design.Advanced healthcare materials · 2026Article
- Targeting fibrosis in the treatment of lower urinary tract dysfunction.The Journal of pathology · 2026Article
- The inflammatory/fibrotic axis across organs: myelofibrosis as a model of reversibility.JCI insight · 2026Review
- Metabolic Endotoxemia Amplifies Estrogen Signaling Through Stromal Crosstalk in Obesity-Associated Breast Cancer.International journal of molecular sciences · 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
- Mechanical gating of tendon fibrogenic transcription in systemic sclerosis.Nature communications · 2026Article
- CXCL4 and CXCL4L1 activate human macrophage via TLR4 signaling to modulate inflammatory responses.Cell insight · 2026Article
- Molecular mechanisms of acute inflammation: systemic responses and kidney-specific pathophysiology.Function (Oxford, England) · 2026Review
- Versican expression from lung fibroblasts suppresses pulmonary fibrosis.Nature communications · 2026Article
- 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
- Aquamin, a marine derived multi-mineral, attenuates toll-like receptor-mediated inflammatory responses in macrophages.Frontiers in immunology · 2026Article
- Article
- Immunopathogenic Mechanisms in Connective Tissue Disease-Associated Interstitial Lung Disease: Incessant Loop of Immunity to Fibrosis.International journal of molecular sciences · 2025Review
- A dermis-on-a-chip model for compound screening.Materials today. Bio · 2025Article
- eNAMPT Is a Novel DAMP and Therapeutic Target in Human and Murine Pulmonary Fibrosis.American journal of respiratory cell and molecular biology · 2025Article
- Unraveling the Role of Metabolic Endotoxemia in Accelerating Breast Tumor Progression.Biomedicines · 2025Article
- Fibroblast-Mediated Macrophage Recruitment Supports Acute Wound Healing.The Journal of investigative dermatology · 2025Article
- Article
- Cell autonomous TLR4 signaling modulates TGF-β induced activation of human cardiac fibroblasts.Heliyon · 2025Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage-associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule. Levels of MD2 and TLR4, and a TLR4-responsive gene signature, were enhanced in SSc skin biopsies. We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis. Fibroblast-specific deletion of TLR4 in mice afforded substantial protection from skin and lung fibrosis. By comparing experimentally generated fibroblast TLR4 gene signatures with SSc skin biopsy gene expression datasets, we identified a subset of SSc patients displaying an activated TLR4 signature. Together, results from these human and mouse studies implicate MD2/TLR4-dependent fibroblast activation as a key driver of persistent organ fibrosis. The results suggest that SSc patients with high TLR4 activity might show optimal therapeutic response to selective inhibitors of MD2/TLR4 complex formation.
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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.