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Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis
  1. Minghua Wu1,
  2. Brian Skaug1,
  3. Xiongjie Bi2,
  4. Tingting Mills3,
  5. Gloria Salazar1,
  6. Xiaodong Zhou1,
  7. John Reveille1,
  8. Sandeep K Agarwal4,
  9. Michael R Blackburn3,
  10. Maureen D Mayes1,
  11. Shervin Assassi1
  1. 1 Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas McGovern Medical School at Houston, Houston, Texas, USA
  2. 2 First Affiliated Hospital of Guangxi University of Science And Technology, Liuzhou, Guangxi, China
  3. 3 Department of Biochemistry and Molecular Biology, University of Texas McGovern Medical School at Houston, Houston, Texas, USA
  4. 4 Department of Medicine, Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, Texas, USA
  1. Correspondence to Dr Minghua Wu, Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA; minghua.wu{at}uth.tmc.edu

Abstract

Objectives There is considerable evidence that implicates dysregulation of type I interferon signalling (or type I IFN signature) in the pathogenesis of systemic sclerosis (SSc). Interferon regulatory factor 7 (IRF7) has been recognised as a master regulator of type I IFN signalling. The objective of this study was to elucidate the role of IRF7 in dermal fibrosis and SSc pathogenesis.

Methods SSc and healthy control skin biopsies were investigated to determine IRF7 expression and activation. The role of IRF7 in fibrosis was investigated using IRF7 knockout (KO) mice in the bleomycin-induced and TSK/+mouse models. In vitro experiments with dermal fibroblasts from patients with SSc and healthy controls were performed.

Results IRF7 expression was significantly upregulated and activated in SSc skin tissue and explanted SSc dermal fibroblasts compared with unaffected, matched controls. Moreover, IRF7 expression was stimulated by IFN-α in dermal fibroblasts. Importantly, IRF7 co-immunoprecipitated with Smad3, a key mediator of transforming growth factor (TGF)-β signalling, and IRF7 knockdown reduced profibrotic factors in SSc fibroblasts. IRF7 KO mice demonstrated attenuated dermal fibrosis and inflammation compared with wild-type mice in response to bleomycin. Specifically, hydroxyproline content, dermal thickness as well as Col1a2, ACTA2 and interleukin-6 mRNA levels were significantly attenuated in IRF7 KO mice skin tissue. Furthermore, IRF7 KO in TSK/+mice attenuated hydroxyproline content, subcutaneous hypodermal thickness, Col1a2 mRNA as well as α-smooth muscle actin and fibronectin expression.

Conclusions IRF7 is upregulated in SSc skin, interacts with Smad3 and potentiates TGF-β-mediated fibrosis, and therefore may represent a promising therapeutic target in SSc.

  • systemic sclerosis
  • fibroblasts
  • autoimmune diseases
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Footnotes

  • Handling editor Josef S Smolen

  • Contributors MW and SA designed the study. MW, BS, XB, TM and SA were involved in acquisition of data. MW, BS, XB, TM, GS, XZ, JR, SKA, MRB, MDM and SA were involved in interpretation of data. All authors were involved in manuscript preparation and have approved the submitted version of the manuscript.

  • Funding This study was supported by Scleroderma Foundation new Investigator Grant (Wu), an Arthritis National Research Foundation grant (Skaug), R01AR073284 (Assassi) and DoD W81XWH-16-1-0296 (Assassi).

  • Competing interests None declared.

  • Ethics approval The study was approved by the institutional review board of the University of Texas Health Science Center at Houston. The animal protocols were institutionally approved by the University of Texas Health Science Center at Houston Animal Care and Use Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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