Journal Article

Tenascin-C drives persistence of organ fibrosis

Lee, Jungwha, Lafyatis, Robert, Hinchcliff, Monique, Tamaki, Zenshiro, Budinger, G. R. Scott, Feghali-Bostwick, Carol, Feng, Gang, Morales-Nebreda, Luisa, Lakota, Katja, Wu, Minghua, Raparia, Kirtee, Varga, John, Bhattacharyya, Swati, Wang, Wenxia, Zhou, Xiaodong

2016

Overview

The factors responsible for maintaining persistent organ fibrosis in systemic sclerosis (SSc) are not known but emerging evidence implicates toll-like receptors (TLRs) in the pathogenesis of SSc. Here we show the expression, mechanism of action and pathogenic role of endogenous TLR activators in skin from patients with SSc, skin fibroblasts, and in mouse models of organ fibrosis. Levels of tenascin-C are elevated in SSc skin biopsy samples, and serum and SSc fibroblasts, and in fibrotic skin tissues from mice. Exogenous tenascin-C stimulates collagen gene expression and myofibroblast transformation via TLR4 signalling. Mice lacking tenascin-C show attenuation of skin and lung fibrosis, and accelerated fibrosis resolution. These results identify tenascin-C as an endogenous danger signal that is upregulated in SSc and drives TLR4-dependent fibroblast activation, and by its persistence impedes fibrosis resolution. Disrupting this fibrosis amplification loop might be a viable strategy for the treatment of SSc. Systemic sclerosis (SSc) is a fibrotic disease affecting multiple organs. Here the authors use patient samples plus mouse studies to show a central role for tenascin C as a TLR4 activator responsible for persistence of fibrosis in the context of SSc and SSc-like disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14 / 14/19 / 631/45/612/1231 / 631/80/86 / 64 / 64/110 / 692/699/1670/122/1801 / 692/700/139/422 / 82/51 / 96 / 96/106 / 96/21 / 96/95 / Adult / Aged / Animal tissues / Animals / Biopsy / Case-Control Studies / Cell Differentiation / Cells, Cultured / Collagen - drug effects / Collagen - genetics / Disease Models, Animal / Female / Fibroblasts - metabolism / Fibrosis - genetics / Fibrosis - metabolism / Gene expression / Gene Expression Regulation / Glycoproteins / Growth factors / Humanities and Social Sciences / Humans / Ligands / Lung - drug effects / Lung - pathology / Male / Mice / Middle Aged / multidisciplinary / Myofibroblasts - drug effects / Pathogenesis / Science / Science (multidisciplinary) / Scleroderma / Scleroderma, Systemic - genetics / Scleroderma, Systemic - metabolism / Scleroderma, Systemic - pathology / Signal Transduction / Skin / Skin - metabolism / Skin - pathology / Tenascin - genetics / Tenascin - metabolism / Tenascin - pharmacology / Toll-Like Receptor 4 - metabolism / Up-Regulation / Variance analysis / Wound healing