A20 suppresses canonical Smad-dependent fibroblast activation: Novel function for an endogenous inflammatory modulator

Swati Bhattacharyya*, Wenxia Wang, Lauren Van Duyn Graham, John Varga

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: The ubiquitin-editing cytosolic enzyme A20, the major negative regulator of toll-like receptor (TLR)-mediated cellular inflammatory responses, has tight genetic linkage with systemic sclerosis (SSc). Because recent studies implicate endogenous ligand-driven TLR signaling in SSc pathogenesis, we sought to investigate the regulation, role and mechanism of action of A20 in skin fibroblasts. Method: A20 expression and the effects of forced A20 expression or siRNA-mediated A20 knockdown on fibrotic responses induced by transforming growth factor-ß (TGF-ß) were evaluated was evaluated in explanted human skin fibroblasts. Additionally, A20 regulation by TGF-ß, and by adiponectin, a pleiotropic adipokine with anti-fibrotic activity, was evaluated. Results: In normal fibroblasts, TGF-ß induced sustained downregulation of A20, and abrogated its TLR4-dependent induction. Forced expression of A20 aborted the stimulation of collagen gene expression and myofibroblast transformation induced by TGF-ß, and disrupted canonical Smad signaling and Smad-dependent transcriptional responses. Conversely, siRNA-mediated knockdown of A20 enhanced the amplitude of fibrotic responses elicited by TGF-ß. Adiponectin, previously shown to block TLR-dependent fibrotic responses, elicited rapid and sustained increase in A20 accumulation in fibroblasts. Conclusion: These results identify the ubiquitin-editing enzyme A20 as a novel endogenous mechanism for negative regulation of fibrotic response intensity. Systemic sclerosis-associated genetic variants of A20 that cause impaired A20 expression or function, combined with direct suppression of A20 by TGF-ß within the fibrotic milieu, might play a significant functional role in persistence of fibrotic responses, while pharmacological augmentation of A20 inhibitory pathway activity might represent a novel therapeutic strategy.

Original languageEnglish (US)
Article number216
JournalArthritis Research and Therapy
Volume18
Issue number1
DOIs
StatePublished - Oct 3 2016

Fingerprint

Transforming Growth Factors
Fibroblasts
Systemic Scleroderma
Toll-Like Receptors
Adiponectin
Ubiquitin
Small Interfering RNA
Skin
Genetic Linkage
Adipokines
Myofibroblasts
Fibroblast Growth Factors
Enzymes
Collagen
Down-Regulation
Pharmacology
Ligands
Gene Expression

Keywords

  • A20
  • Adiponectin
  • Fibrosis
  • IL-6
  • LPS
  • Systemic sclerosis
  • TGF-ß
  • TLR4
  • TNFAIP3
  • Type I collagen

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

Cite this

@article{24326c71104f46908274747aa49ad1db,
title = "A20 suppresses canonical Smad-dependent fibroblast activation: Novel function for an endogenous inflammatory modulator",
abstract = "Background: The ubiquitin-editing cytosolic enzyme A20, the major negative regulator of toll-like receptor (TLR)-mediated cellular inflammatory responses, has tight genetic linkage with systemic sclerosis (SSc). Because recent studies implicate endogenous ligand-driven TLR signaling in SSc pathogenesis, we sought to investigate the regulation, role and mechanism of action of A20 in skin fibroblasts. Method: A20 expression and the effects of forced A20 expression or siRNA-mediated A20 knockdown on fibrotic responses induced by transforming growth factor-{\ss} (TGF-{\ss}) were evaluated was evaluated in explanted human skin fibroblasts. Additionally, A20 regulation by TGF-{\ss}, and by adiponectin, a pleiotropic adipokine with anti-fibrotic activity, was evaluated. Results: In normal fibroblasts, TGF-{\ss} induced sustained downregulation of A20, and abrogated its TLR4-dependent induction. Forced expression of A20 aborted the stimulation of collagen gene expression and myofibroblast transformation induced by TGF-{\ss}, and disrupted canonical Smad signaling and Smad-dependent transcriptional responses. Conversely, siRNA-mediated knockdown of A20 enhanced the amplitude of fibrotic responses elicited by TGF-{\ss}. Adiponectin, previously shown to block TLR-dependent fibrotic responses, elicited rapid and sustained increase in A20 accumulation in fibroblasts. Conclusion: These results identify the ubiquitin-editing enzyme A20 as a novel endogenous mechanism for negative regulation of fibrotic response intensity. Systemic sclerosis-associated genetic variants of A20 that cause impaired A20 expression or function, combined with direct suppression of A20 by TGF-{\ss} within the fibrotic milieu, might play a significant functional role in persistence of fibrotic responses, while pharmacological augmentation of A20 inhibitory pathway activity might represent a novel therapeutic strategy.",
keywords = "A20, Adiponectin, Fibrosis, IL-6, LPS, Systemic sclerosis, TGF-{\ss}, TLR4, TNFAIP3, Type I collagen",
author = "Swati Bhattacharyya and Wenxia Wang and Graham, {Lauren Van Duyn} and John Varga",
year = "2016",
month = "10",
day = "3",
doi = "10.1186/s13075-016-1118-7",
language = "English (US)",
volume = "18",
journal = "Arthritis Research and Therapy",
issn = "1478-6354",
publisher = "BioMed Central",
number = "1",

}

A20 suppresses canonical Smad-dependent fibroblast activation : Novel function for an endogenous inflammatory modulator. / Bhattacharyya, Swati; Wang, Wenxia; Graham, Lauren Van Duyn; Varga, John.

In: Arthritis Research and Therapy, Vol. 18, No. 1, 216, 03.10.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A20 suppresses canonical Smad-dependent fibroblast activation

T2 - Novel function for an endogenous inflammatory modulator

AU - Bhattacharyya, Swati

AU - Wang, Wenxia

AU - Graham, Lauren Van Duyn

AU - Varga, John

PY - 2016/10/3

Y1 - 2016/10/3

N2 - Background: The ubiquitin-editing cytosolic enzyme A20, the major negative regulator of toll-like receptor (TLR)-mediated cellular inflammatory responses, has tight genetic linkage with systemic sclerosis (SSc). Because recent studies implicate endogenous ligand-driven TLR signaling in SSc pathogenesis, we sought to investigate the regulation, role and mechanism of action of A20 in skin fibroblasts. Method: A20 expression and the effects of forced A20 expression or siRNA-mediated A20 knockdown on fibrotic responses induced by transforming growth factor-ß (TGF-ß) were evaluated was evaluated in explanted human skin fibroblasts. Additionally, A20 regulation by TGF-ß, and by adiponectin, a pleiotropic adipokine with anti-fibrotic activity, was evaluated. Results: In normal fibroblasts, TGF-ß induced sustained downregulation of A20, and abrogated its TLR4-dependent induction. Forced expression of A20 aborted the stimulation of collagen gene expression and myofibroblast transformation induced by TGF-ß, and disrupted canonical Smad signaling and Smad-dependent transcriptional responses. Conversely, siRNA-mediated knockdown of A20 enhanced the amplitude of fibrotic responses elicited by TGF-ß. Adiponectin, previously shown to block TLR-dependent fibrotic responses, elicited rapid and sustained increase in A20 accumulation in fibroblasts. Conclusion: These results identify the ubiquitin-editing enzyme A20 as a novel endogenous mechanism for negative regulation of fibrotic response intensity. Systemic sclerosis-associated genetic variants of A20 that cause impaired A20 expression or function, combined with direct suppression of A20 by TGF-ß within the fibrotic milieu, might play a significant functional role in persistence of fibrotic responses, while pharmacological augmentation of A20 inhibitory pathway activity might represent a novel therapeutic strategy.

AB - Background: The ubiquitin-editing cytosolic enzyme A20, the major negative regulator of toll-like receptor (TLR)-mediated cellular inflammatory responses, has tight genetic linkage with systemic sclerosis (SSc). Because recent studies implicate endogenous ligand-driven TLR signaling in SSc pathogenesis, we sought to investigate the regulation, role and mechanism of action of A20 in skin fibroblasts. Method: A20 expression and the effects of forced A20 expression or siRNA-mediated A20 knockdown on fibrotic responses induced by transforming growth factor-ß (TGF-ß) were evaluated was evaluated in explanted human skin fibroblasts. Additionally, A20 regulation by TGF-ß, and by adiponectin, a pleiotropic adipokine with anti-fibrotic activity, was evaluated. Results: In normal fibroblasts, TGF-ß induced sustained downregulation of A20, and abrogated its TLR4-dependent induction. Forced expression of A20 aborted the stimulation of collagen gene expression and myofibroblast transformation induced by TGF-ß, and disrupted canonical Smad signaling and Smad-dependent transcriptional responses. Conversely, siRNA-mediated knockdown of A20 enhanced the amplitude of fibrotic responses elicited by TGF-ß. Adiponectin, previously shown to block TLR-dependent fibrotic responses, elicited rapid and sustained increase in A20 accumulation in fibroblasts. Conclusion: These results identify the ubiquitin-editing enzyme A20 as a novel endogenous mechanism for negative regulation of fibrotic response intensity. Systemic sclerosis-associated genetic variants of A20 that cause impaired A20 expression or function, combined with direct suppression of A20 by TGF-ß within the fibrotic milieu, might play a significant functional role in persistence of fibrotic responses, while pharmacological augmentation of A20 inhibitory pathway activity might represent a novel therapeutic strategy.

KW - A20

KW - Adiponectin

KW - Fibrosis

KW - IL-6

KW - LPS

KW - Systemic sclerosis

KW - TGF-ß

KW - TLR4

KW - TNFAIP3

KW - Type I collagen

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U2 - 10.1186/s13075-016-1118-7

DO - 10.1186/s13075-016-1118-7

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