Endogenous ligands of TLR4 promote unresolving tissue fibrosis

Implications for systemic sclerosis and its targeted therapy

Swati Bhattacharyya*, John Varga

*Corresponding author for this work

Research output: Contribution to journalReview article

12 Citations (Scopus)

Abstract

Fibrosis, the hallmark of scleroderma or systemic sclerosis (SSc), is a complex, dynamic and generally irreversible pathophysiological process that leads to tissue disruption, and lacks effective therapy. While early-stage fibrosis resembles normal wound healing, in SSc fibrosis fails to resolve. Innate immune signaling via toll-like receptors (TLRs) has recently emerged as a key driver of persistent fibrotic response in SSc. Recurrent injury in genetically predisposed individual causes generation of “damage-associated molecular patterns” (DAMPs) such as fibronectin-EDA and tenascin-C. Sensing of these danger signals by TLR4 on resident cells elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation, and appears to sensitize fibroblasts to the profibrotic stimulatory effect of TGF-β. Thus, DAMPs induce TLR4-mediated innate immune signaling on resident mesenchymal cells which drives the emergence and persistence of fibrotic cells in tissues, and underlies the switch from a self-limited repair response to non-resolving pathological fibrosis characteristic of SSc. In this review, we present current views of the DAMP-TLR4 axis in driving sustained fibroblasts activation and its pathogenic roles in fibrosis progression in SSc, and potential anti-fibrotic approaches for selective therapeutic targeting of TLR4 signaling.

Original languageEnglish (US)
Pages (from-to)9-17
Number of pages9
JournalImmunology Letters
Volume195
DOIs
StatePublished - Mar 1 2018

Fingerprint

Systemic Scleroderma
Fibrosis
Ligands
Fibroblasts
Therapeutics
Tenascin
Myofibroblasts
Toll-Like Receptors
Fibronectins
Wound Healing
Gene Expression
Wounds and Injuries

Keywords

  • A20
  • Damage-associated molecular patterns (DAMP)
  • Fibroblast
  • Fibronectin-EDA
  • Fibrosis
  • Innate immunity
  • Scleroderma
  • Systemic sclerosis
  • TNFAIP3/A20
  • Tenascin-C
  • Toll-like receptor (TLR)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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title = "Endogenous ligands of TLR4 promote unresolving tissue fibrosis: Implications for systemic sclerosis and its targeted therapy",
abstract = "Fibrosis, the hallmark of scleroderma or systemic sclerosis (SSc), is a complex, dynamic and generally irreversible pathophysiological process that leads to tissue disruption, and lacks effective therapy. While early-stage fibrosis resembles normal wound healing, in SSc fibrosis fails to resolve. Innate immune signaling via toll-like receptors (TLRs) has recently emerged as a key driver of persistent fibrotic response in SSc. Recurrent injury in genetically predisposed individual causes generation of “damage-associated molecular patterns” (DAMPs) such as fibronectin-EDA and tenascin-C. Sensing of these danger signals by TLR4 on resident cells elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation, and appears to sensitize fibroblasts to the profibrotic stimulatory effect of TGF-β. Thus, DAMPs induce TLR4-mediated innate immune signaling on resident mesenchymal cells which drives the emergence and persistence of fibrotic cells in tissues, and underlies the switch from a self-limited repair response to non-resolving pathological fibrosis characteristic of SSc. In this review, we present current views of the DAMP-TLR4 axis in driving sustained fibroblasts activation and its pathogenic roles in fibrosis progression in SSc, and potential anti-fibrotic approaches for selective therapeutic targeting of TLR4 signaling.",
keywords = "A20, Damage-associated molecular patterns (DAMP), Fibroblast, Fibronectin-EDA, Fibrosis, Innate immunity, Scleroderma, Systemic sclerosis, TNFAIP3/A20, Tenascin-C, Toll-like receptor (TLR)",
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T1 - Endogenous ligands of TLR4 promote unresolving tissue fibrosis

T2 - Implications for systemic sclerosis and its targeted therapy

AU - Bhattacharyya, Swati

AU - Varga, John

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Fibrosis, the hallmark of scleroderma or systemic sclerosis (SSc), is a complex, dynamic and generally irreversible pathophysiological process that leads to tissue disruption, and lacks effective therapy. While early-stage fibrosis resembles normal wound healing, in SSc fibrosis fails to resolve. Innate immune signaling via toll-like receptors (TLRs) has recently emerged as a key driver of persistent fibrotic response in SSc. Recurrent injury in genetically predisposed individual causes generation of “damage-associated molecular patterns” (DAMPs) such as fibronectin-EDA and tenascin-C. Sensing of these danger signals by TLR4 on resident cells elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation, and appears to sensitize fibroblasts to the profibrotic stimulatory effect of TGF-β. Thus, DAMPs induce TLR4-mediated innate immune signaling on resident mesenchymal cells which drives the emergence and persistence of fibrotic cells in tissues, and underlies the switch from a self-limited repair response to non-resolving pathological fibrosis characteristic of SSc. In this review, we present current views of the DAMP-TLR4 axis in driving sustained fibroblasts activation and its pathogenic roles in fibrosis progression in SSc, and potential anti-fibrotic approaches for selective therapeutic targeting of TLR4 signaling.

AB - Fibrosis, the hallmark of scleroderma or systemic sclerosis (SSc), is a complex, dynamic and generally irreversible pathophysiological process that leads to tissue disruption, and lacks effective therapy. While early-stage fibrosis resembles normal wound healing, in SSc fibrosis fails to resolve. Innate immune signaling via toll-like receptors (TLRs) has recently emerged as a key driver of persistent fibrotic response in SSc. Recurrent injury in genetically predisposed individual causes generation of “damage-associated molecular patterns” (DAMPs) such as fibronectin-EDA and tenascin-C. Sensing of these danger signals by TLR4 on resident cells elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation, and appears to sensitize fibroblasts to the profibrotic stimulatory effect of TGF-β. Thus, DAMPs induce TLR4-mediated innate immune signaling on resident mesenchymal cells which drives the emergence and persistence of fibrotic cells in tissues, and underlies the switch from a self-limited repair response to non-resolving pathological fibrosis characteristic of SSc. In this review, we present current views of the DAMP-TLR4 axis in driving sustained fibroblasts activation and its pathogenic roles in fibrosis progression in SSc, and potential anti-fibrotic approaches for selective therapeutic targeting of TLR4 signaling.

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KW - Fibronectin-EDA

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KW - Innate immunity

KW - Scleroderma

KW - Systemic sclerosis

KW - TNFAIP3/A20

KW - Tenascin-C

KW - Toll-like receptor (TLR)

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