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

9 Scopus citations

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

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

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