title: Tenascin-C drives persistence of organ fibrosis.
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.
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Wang
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Morales-Nebreda
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Feng
authors.affiliation: University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Minghua
authors.initials: M
authors.lastname: Wu
authors.affiliation: University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts 02215, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Jungwha
authors.initials: J
authors.lastname: Lee
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Hinchcliff
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina 29225, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Katja
authors.initials: K
authors.lastname: Lakota
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Kirtee
authors.initials: K
authors.lastname: Raparia
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Zenshiro
authors.initials: Z
authors.lastname: Tamaki
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D058628:Myofibroblasts / Q000187:drug effects; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D019063:Tenascin / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019063:Tenascin; D051197:Toll-Like Receptor 4; D003094:Collagen