Tenascin-C drives persistence of organ fibrosis

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

*Corresponding author for this work

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number11703
JournalNature communications
Volume7
DOIs
StatePublished - Jun 3 2016

Fingerprint

Tenascin
fibrosis
Systemic Scleroderma
organs
Skin
Fibrosis
Fibroblasts
fibroblasts
Toll-Like Receptors
mice
Biopsy
disrupting
pathogenesis
Gene expression
gene expression
Amplification
collagens
Myofibroblasts
Collagen
serums

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Bhattacharyya, Swati ; Wang, Wenxia ; Morales-Nebreda, Luisa ; Feng, Gang ; Wu, Minghua ; Zhou, Xiaodong ; Lafyatis, Robert ; Lee, Jungwha ; Hinchcliff, Monique ; Feghali-Bostwick, Carol ; Lakota, Katja ; Budinger, G. R Scott ; Raparia, Kirtee ; Tamaki, Zenshiro ; Varga, John. / Tenascin-C drives persistence of organ fibrosis. In: Nature communications. 2016 ; Vol. 7.
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Bhattacharyya, S, Wang, W, Morales-Nebreda, L, Feng, G, Wu, M, Zhou, X, Lafyatis, R, Lee, J, Hinchcliff, M, Feghali-Bostwick, C, Lakota, K, Budinger, GRS, Raparia, K, Tamaki, Z & Varga, J 2016, 'Tenascin-C drives persistence of organ fibrosis', Nature communications, vol. 7, 11703. https://doi.org/10.1038/ncomms11703

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

In: Nature communications, Vol. 7, 11703, 03.06.2016.

Research output: Contribution to journalArticle

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AU - Lakota, Katja

AU - Budinger, G. R Scott

AU - Raparia, Kirtee

AU - Tamaki, Zenshiro

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Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, Zhou X et al. Tenascin-C drives persistence of organ fibrosis. Nature communications. 2016 Jun 3;7. 11703. https://doi.org/10.1038/ncomms11703