Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis. Issue 11 (22nd August 2019)

• Record Type: Journal Article
• Authors: Wu, Minghua; Skaug, Brian; Bi, Xiongjie; Mills, Tingting; Salazar, Gloria; Zhou, Xiaodong; Reveille, John; Agarwal, Sandeep K; Blackburn, Michael R; Mayes, Maureen D; Assassi, Shervin
• Is Part Of: Annals of the rheumatic diseases. Volume 78:Issue 11(2019)
• Page Start: 1583
• Page End: 1591
• Publication Date: 2019-08-22
• Subjects: systemic sclerosis -- fibroblasts -- autoimmune diseases; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-215208
• Languages: English
• ISSNs: 0003-4967

Abstract

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.