Emerging Roles of Innate Immune Signaling and Toll-Like Receptors in Fibrosis and Systemic Sclerosis

Swati Bhattacharyya*, John Varga

*Corresponding author for this work

Research output: Contribution to journalReview article

40 Citations (Scopus)

Abstract

Pathological fibrosis is a distinguishing hallmark of systemic sclerosis (SSc) as well as a number of more common conditions. Fibrosis is a complex and dynamic process associated with immune dysregulation, vasculopathy, and uncontrolled extracellular matrix production leading to intractable scar formation in the skin and internal organs. Persistent or recurrent chemical, infectious, mechanical, or autoimmune injury in genetically predisposed individuals causes sustained fibroblasts activation. Innate immune signaling via toll-like receptors (TLRs) is increasingly recognized as a key player driving the persistent fibrotic response in SSc. In particular, expression of TLR4 as well as its endogenous ligands are elevated in lesional tissue from patients with SSc. Ligand-induced TLR4 activation elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation. Furthermore, TLR4 appears to sensitize fibroblasts to the profibrotic stimulatory effect of transforming growth factor-β. This review highlights recent advances and emerging paradigms for understanding the regulation, complex functional roles, and therapeutic potential of TLRs in SSc pathogenesis.

Original languageEnglish (US)
JournalCurrent Rheumatology Reports
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Systemic Scleroderma
Toll-Like Receptors
Fibrosis
Fibroblasts
Ligands
Myofibroblasts
Transforming Growth Factors
Cicatrix
Extracellular Matrix
Gene Expression
Skin
Wounds and Injuries
Therapeutics

Keywords

  • Fibroblast
  • Fibrosis
  • Fn-EDA
  • SSc
  • Scleroderma
  • Systemic sclerosis
  • TGF-ß
  • Toll-like receptor 4

ASJC Scopus subject areas

  • Rheumatology

Cite this

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title = "Emerging Roles of Innate Immune Signaling and Toll-Like Receptors in Fibrosis and Systemic Sclerosis",
abstract = "Pathological fibrosis is a distinguishing hallmark of systemic sclerosis (SSc) as well as a number of more common conditions. Fibrosis is a complex and dynamic process associated with immune dysregulation, vasculopathy, and uncontrolled extracellular matrix production leading to intractable scar formation in the skin and internal organs. Persistent or recurrent chemical, infectious, mechanical, or autoimmune injury in genetically predisposed individuals causes sustained fibroblasts activation. Innate immune signaling via toll-like receptors (TLRs) is increasingly recognized as a key player driving the persistent fibrotic response in SSc. In particular, expression of TLR4 as well as its endogenous ligands are elevated in lesional tissue from patients with SSc. Ligand-induced TLR4 activation elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation. Furthermore, TLR4 appears to sensitize fibroblasts to the profibrotic stimulatory effect of transforming growth factor-β. This review highlights recent advances and emerging paradigms for understanding the regulation, complex functional roles, and therapeutic potential of TLRs in SSc pathogenesis.",
keywords = "Fibroblast, Fibrosis, Fn-EDA, SSc, Scleroderma, Systemic sclerosis, TGF-{\ss}, Toll-like receptor 4",
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N2 - Pathological fibrosis is a distinguishing hallmark of systemic sclerosis (SSc) as well as a number of more common conditions. Fibrosis is a complex and dynamic process associated with immune dysregulation, vasculopathy, and uncontrolled extracellular matrix production leading to intractable scar formation in the skin and internal organs. Persistent or recurrent chemical, infectious, mechanical, or autoimmune injury in genetically predisposed individuals causes sustained fibroblasts activation. Innate immune signaling via toll-like receptors (TLRs) is increasingly recognized as a key player driving the persistent fibrotic response in SSc. In particular, expression of TLR4 as well as its endogenous ligands are elevated in lesional tissue from patients with SSc. Ligand-induced TLR4 activation elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation. Furthermore, TLR4 appears to sensitize fibroblasts to the profibrotic stimulatory effect of transforming growth factor-β. This review highlights recent advances and emerging paradigms for understanding the regulation, complex functional roles, and therapeutic potential of TLRs in SSc pathogenesis.

AB - Pathological fibrosis is a distinguishing hallmark of systemic sclerosis (SSc) as well as a number of more common conditions. Fibrosis is a complex and dynamic process associated with immune dysregulation, vasculopathy, and uncontrolled extracellular matrix production leading to intractable scar formation in the skin and internal organs. Persistent or recurrent chemical, infectious, mechanical, or autoimmune injury in genetically predisposed individuals causes sustained fibroblasts activation. Innate immune signaling via toll-like receptors (TLRs) is increasingly recognized as a key player driving the persistent fibrotic response in SSc. In particular, expression of TLR4 as well as its endogenous ligands are elevated in lesional tissue from patients with SSc. Ligand-induced TLR4 activation elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation. Furthermore, TLR4 appears to sensitize fibroblasts to the profibrotic stimulatory effect of transforming growth factor-β. This review highlights recent advances and emerging paradigms for understanding the regulation, complex functional roles, and therapeutic potential of TLRs in SSc pathogenesis.

KW - Fibroblast

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KW - Toll-like receptor 4

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