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 and John Varga ()
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Swati Bhattacharyya: Northwestern University Feinberg School of Medicine
Wenxia Wang: Northwestern University Feinberg School of Medicine
Luisa Morales-Nebreda: Northwestern University Feinberg School of Medicine
Gang Feng: Northwestern University Feinberg School of Medicine
Minghua Wu: University of Texas Medical School at Houston
Xiaodong Zhou: University of Texas Medical School at Houston
Robert Lafyatis: Boston University School of Medicine
Jungwha Lee: Northwestern University Feinberg School of Medicine
Monique Hinchcliff: Northwestern University Feinberg School of Medicine
Carol Feghali-Bostwick: Medical University of South Carolina
Katja Lakota: Northwestern University Feinberg School of Medicine
G. R. Scott Budinger: Northwestern University Feinberg School of Medicine
Kirtee Raparia: Northwestern University Feinberg School of Medicine
Zenshiro Tamaki: Northwestern University Feinberg School of Medicine
John Varga: Northwestern University Feinberg School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11703

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