title: Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma.
abstract: Because recent studies implicate Toll-like receptors (TLRs) in the pathogenesis of fibrosis, we sought to investigate the in vitro and in vivo role and mechanism of TLR4-mediated fibroblast responses in fibrogenesis. We found that TLR4 was constitutively expressed, and accumulation of endogenous TLR4 ligands significantly elevated, in lesional skin and lung tissues from patients with scleroderma. Activation of TLR4 signaling in explanted fibroblasts resulted in enhanced collagen synthesis and increased expression of multiple genes involved in tissue remodeling and extracellular matrix homeostasis. Moreover, TLR4 dramatically enhanced the sensitivity of fibroblasts to the stimulatory effect of transforming growth factor-β1. These profibrotic responses were abrogated by both genetic and pharmacological disruption of TLR4 signaling in vitro, and skin fibrosis induced by bleomycin in vivo was attenuated in mice harboring a mutated TLR4. Activation of TLR4 in fibroblasts augmented the intensity of canonical Smad signaling, and was accompanied by suppression of anti-fibrotic microRNA expression. Together, these results suggest a novel model to account for persistent fibrogenesis in scleroderma, in which activation of fibroblast TLR4 signaling, triggered by damage-associated endogenous TLR4 ligands, results in augmented transforming growth factor-β1 sensitivity with increased matrix production and progressive connective tissue remodeling. Under these conditions, fibroblast TLR4 serves as the switch for converting self-limited tissue repair into intractable fibrosis.
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. s-bhattacharyya@northwestern.edu
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kelley
authors.forename: Denisa S
authors.initials: DS
authors.lastname: Melichian
authors.forename: Zenshiro
authors.initials: Z
authors.lastname: Tamaki
authors.forename: Feng
authors.initials: F
authors.lastname: Fang
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Su
authors.forename: Gilbert
authors.initials: G
authors.lastname: Feng
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.forename: Timothy
authors.initials: T
authors.lastname: Radstake
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001706:Biopsy; D001761:Bleomycin; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D008024:Ligands; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D008024:Ligands; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D003094:Collagen