TY - JOUR
T1 - Tenascin-C drives persistence of organ fibrosis
AU - Bhattacharyya, Swati
AU - Wang, Wenxia
AU - Morales-Nebreda, Luisa
AU - Feng, Gang
AU - Wu, Minghua
AU - Zhou, Xiaodong
AU - Lafyatis, Robert
AU - Lee, Jungwha
AU - Hinchcliff, Monique
AU - Feghali-Bostwick, Carol
AU - Lakota, Katja
AU - Budinger, G. R Scott
AU - Raparia, Kirtee
AU - Tamaki, Zenshiro
AU - Varga, John
N1 - Funding Information:
We are grateful to Sofia Hussein, members of the Varga lab, the staffs of the Transgenic and Targeted Mutagenesis Laboratory, Mouse Histology & Phenotyping Laboratory (MHPL), Skin Diseases Research Core, and Northwestern University Imaging Core for excellent technical support, and Drs Robert Schleimer and Kim Midwood for helpful discussions. TLR4fl/fl mice were a generous gift from Dr Christopher Karp (Cincinnati Childrens Hospital). Support was received from grant AR-42309 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and K24 AR060297. Gang Feng is partially supported by the NCI Cancer Support Grant (NCI CA060553) and the National Center for Advancing Translational Sciences Grant (8UL1TR000150).
PY - 2016/6/3
Y1 - 2016/6/3
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms11703
DO - 10.1038/ncomms11703
M3 - Article
C2 - 27256716
AN - SCOPUS:84973360161
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 11703
ER -