Toll-like receptor-4 signaling drives persistent fibroblast activation and prevents fibrosis resolution in scleroderma

Swati Bhattacharyya*, Kim S. Midwood, Hang Yin, John Varga

*Corresponding author for this work

Research output: Contribution to journalReview article

8 Citations (Scopus)

Abstract

Significance: This review provides current overview of the emerging role of innate immunity in driving fibrosis, and preventing its resolution, in scleroderma (systemic sclerosis, SSc). Understanding the mechanisms of dysregulated innate immunity in fibrosis and SSc will provide opportunities for therapeutic interventions using novel agents and repurposed existing drugs. Recent Advances: New insights from genomic and genetic studies implicate components of innate immune signaling such as pattern recognition receptors (PRRs), downstream signaling intermediates, and endogenous inhibitors, in fibrosis in SSc. Recent studies distinguish innate immune signaling in tissue-resident myofibroblasts and bone marrow-derived immune cells and define their roles in the development and persistence of tissue fibrosis. Critical Issues: Activation of toll-like receptors (TLRs) and other PRR mechanisms occurs in resident nonimmune cells within injured tissue microenvironments. These cells respond to damage-associated molecular patterns (DAMPs), such as tenascin-C that are recognized as danger signals, and elicit matrix production, cytokine secretion, and myofibroblast transformation and survival. When these responses persist due to constitutive TLR activation or impaired termination by endogenous inhibitors, they interfere with fibrosis resolution. The genetic basis and molecular mechanisms of these phenomena in the context of fibrosis are under current investigation. Future Directions: Precise delineation of the pathogenic DAMPs, their interaction with TLRs and other PRRs, the downstream signaling pathways and transcriptional events, and the fibroblast-specific regulation and function of endogenous inhibitors of innate immunity, will form the foundation for innovative targeted therapies to block fibrosis by reestablishing balanced innate immune signaling in fibroblasts.

Original languageEnglish (US)
Pages (from-to)356-369
Number of pages14
JournalAdvances in Wound Care
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2017

Fingerprint

Toll-Like Receptor 4
Fibrosis
Fibroblasts
Pattern Recognition Receptors
Systemic Scleroderma
Toll-Like Receptors
Innate Immunity
Myofibroblasts
Drug Repositioning
Tenascin
Investigational Therapies
Molecular Biology
Bone Marrow
Cytokines

Keywords

  • A20
  • DAMP
  • SSc
  • TLR
  • TNFAIP3/A20
  • fibroblast
  • fibronectin- EDA
  • fibrosis
  • systemic sclerosis
  • tenascin-C

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

@article{dee94861b0f345359c19842f021eb661,
title = "Toll-like receptor-4 signaling drives persistent fibroblast activation and prevents fibrosis resolution in scleroderma",
abstract = "Significance: This review provides current overview of the emerging role of innate immunity in driving fibrosis, and preventing its resolution, in scleroderma (systemic sclerosis, SSc). Understanding the mechanisms of dysregulated innate immunity in fibrosis and SSc will provide opportunities for therapeutic interventions using novel agents and repurposed existing drugs. Recent Advances: New insights from genomic and genetic studies implicate components of innate immune signaling such as pattern recognition receptors (PRRs), downstream signaling intermediates, and endogenous inhibitors, in fibrosis in SSc. Recent studies distinguish innate immune signaling in tissue-resident myofibroblasts and bone marrow-derived immune cells and define their roles in the development and persistence of tissue fibrosis. Critical Issues: Activation of toll-like receptors (TLRs) and other PRR mechanisms occurs in resident nonimmune cells within injured tissue microenvironments. These cells respond to damage-associated molecular patterns (DAMPs), such as tenascin-C that are recognized as danger signals, and elicit matrix production, cytokine secretion, and myofibroblast transformation and survival. When these responses persist due to constitutive TLR activation or impaired termination by endogenous inhibitors, they interfere with fibrosis resolution. The genetic basis and molecular mechanisms of these phenomena in the context of fibrosis are under current investigation. Future Directions: Precise delineation of the pathogenic DAMPs, their interaction with TLRs and other PRRs, the downstream signaling pathways and transcriptional events, and the fibroblast-specific regulation and function of endogenous inhibitors of innate immunity, will form the foundation for innovative targeted therapies to block fibrosis by reestablishing balanced innate immune signaling in fibroblasts.",
keywords = "A20, DAMP, SSc, TLR, TNFAIP3/A20, fibroblast, fibronectin- EDA, fibrosis, systemic sclerosis, tenascin-C",
author = "Swati Bhattacharyya and Midwood, {Kim S.} and Hang Yin and John Varga",
year = "2017",
month = "10",
day = "1",
doi = "10.1089/wound.2017.0732",
language = "English (US)",
volume = "6",
pages = "356--369",
journal = "Advances in Wound Care",
issn = "2162-1918",
publisher = "Mary Ann Liebert Inc.",
number = "10",

}

Toll-like receptor-4 signaling drives persistent fibroblast activation and prevents fibrosis resolution in scleroderma. / Bhattacharyya, Swati; Midwood, Kim S.; Yin, Hang; Varga, John.

In: Advances in Wound Care, Vol. 6, No. 10, 01.10.2017, p. 356-369.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Toll-like receptor-4 signaling drives persistent fibroblast activation and prevents fibrosis resolution in scleroderma

AU - Bhattacharyya, Swati

AU - Midwood, Kim S.

AU - Yin, Hang

AU - Varga, John

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Significance: This review provides current overview of the emerging role of innate immunity in driving fibrosis, and preventing its resolution, in scleroderma (systemic sclerosis, SSc). Understanding the mechanisms of dysregulated innate immunity in fibrosis and SSc will provide opportunities for therapeutic interventions using novel agents and repurposed existing drugs. Recent Advances: New insights from genomic and genetic studies implicate components of innate immune signaling such as pattern recognition receptors (PRRs), downstream signaling intermediates, and endogenous inhibitors, in fibrosis in SSc. Recent studies distinguish innate immune signaling in tissue-resident myofibroblasts and bone marrow-derived immune cells and define their roles in the development and persistence of tissue fibrosis. Critical Issues: Activation of toll-like receptors (TLRs) and other PRR mechanisms occurs in resident nonimmune cells within injured tissue microenvironments. These cells respond to damage-associated molecular patterns (DAMPs), such as tenascin-C that are recognized as danger signals, and elicit matrix production, cytokine secretion, and myofibroblast transformation and survival. When these responses persist due to constitutive TLR activation or impaired termination by endogenous inhibitors, they interfere with fibrosis resolution. The genetic basis and molecular mechanisms of these phenomena in the context of fibrosis are under current investigation. Future Directions: Precise delineation of the pathogenic DAMPs, their interaction with TLRs and other PRRs, the downstream signaling pathways and transcriptional events, and the fibroblast-specific regulation and function of endogenous inhibitors of innate immunity, will form the foundation for innovative targeted therapies to block fibrosis by reestablishing balanced innate immune signaling in fibroblasts.

AB - Significance: This review provides current overview of the emerging role of innate immunity in driving fibrosis, and preventing its resolution, in scleroderma (systemic sclerosis, SSc). Understanding the mechanisms of dysregulated innate immunity in fibrosis and SSc will provide opportunities for therapeutic interventions using novel agents and repurposed existing drugs. Recent Advances: New insights from genomic and genetic studies implicate components of innate immune signaling such as pattern recognition receptors (PRRs), downstream signaling intermediates, and endogenous inhibitors, in fibrosis in SSc. Recent studies distinguish innate immune signaling in tissue-resident myofibroblasts and bone marrow-derived immune cells and define their roles in the development and persistence of tissue fibrosis. Critical Issues: Activation of toll-like receptors (TLRs) and other PRR mechanisms occurs in resident nonimmune cells within injured tissue microenvironments. These cells respond to damage-associated molecular patterns (DAMPs), such as tenascin-C that are recognized as danger signals, and elicit matrix production, cytokine secretion, and myofibroblast transformation and survival. When these responses persist due to constitutive TLR activation or impaired termination by endogenous inhibitors, they interfere with fibrosis resolution. The genetic basis and molecular mechanisms of these phenomena in the context of fibrosis are under current investigation. Future Directions: Precise delineation of the pathogenic DAMPs, their interaction with TLRs and other PRRs, the downstream signaling pathways and transcriptional events, and the fibroblast-specific regulation and function of endogenous inhibitors of innate immunity, will form the foundation for innovative targeted therapies to block fibrosis by reestablishing balanced innate immune signaling in fibroblasts.

KW - A20

KW - DAMP

KW - SSc

KW - TLR

KW - TNFAIP3/A20

KW - fibroblast

KW - fibronectin- EDA

KW - fibrosis

KW - systemic sclerosis

KW - tenascin-C

UR - http://www.scopus.com/inward/record.url?scp=85030563214&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030563214&partnerID=8YFLogxK

U2 - 10.1089/wound.2017.0732

DO - 10.1089/wound.2017.0732

M3 - Review article

C2 - 29062592

AN - SCOPUS:85030563214

VL - 6

SP - 356

EP - 369

JO - Advances in Wound Care

JF - Advances in Wound Care

SN - 2162-1918

IS - 10

ER -