Toll-like receptor 4 signaling augments transforming growth factor-β responses: A novel mechanism for maintaining and amplifying fibrosis in scleroderma

Swati Bhattacharyya*, Kathleen Kelley, Denisa S. Melichian, Zenshiro Tamaki, Feng Fang, Yunyun Su, Gilbert Feng, Richard M Pope, GR Scott Budinger, Gökhan M. Mutlu, Robert Lafyatis, Timothy Radstake, Carol Feghali-Bostwick, John Varga

*Corresponding author for this work

Research output: Contribution to journalArticle

133 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)192-205
Number of pages14
JournalAmerican Journal of Pathology
Volume182
Issue number1
DOIs
StatePublished - Jan 1 2013

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Toll-Like Receptor 4
Transforming Growth Factors
Fibrosis
Fibroblasts
Ligands
Skin
Toll-Like Receptors
MicroRNAs
Connective Tissue
Extracellular Matrix
Homeostasis
Collagen
Pharmacology
Gene Expression
Lung

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Bhattacharyya, Swati ; Kelley, Kathleen ; Melichian, Denisa S. ; Tamaki, Zenshiro ; Fang, Feng ; Su, Yunyun ; Feng, Gilbert ; Pope, Richard M ; Budinger, GR Scott ; Mutlu, Gökhan M. ; Lafyatis, Robert ; Radstake, Timothy ; Feghali-Bostwick, Carol ; Varga, John. / Toll-like receptor 4 signaling augments transforming growth factor-β responses : A novel mechanism for maintaining and amplifying fibrosis in scleroderma. In: American Journal of Pathology. 2013 ; Vol. 182, No. 1. pp. 192-205.
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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.",
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Toll-like receptor 4 signaling augments transforming growth factor-β responses : A novel mechanism for maintaining and amplifying fibrosis in scleroderma. / Bhattacharyya, Swati; Kelley, Kathleen; Melichian, Denisa S.; Tamaki, Zenshiro; Fang, Feng; Su, Yunyun; Feng, Gilbert; Pope, Richard M; Budinger, GR Scott; Mutlu, Gökhan M.; Lafyatis, Robert; Radstake, Timothy; Feghali-Bostwick, Carol; Varga, John.

In: American Journal of Pathology, Vol. 182, No. 1, 01.01.2013, p. 192-205.

Research output: Contribution to journalArticle

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AB - 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.

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