Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas McGovern Medical School at Houston, Houston, Texas, USA
Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas McGovern Medical School at Houston, Houston, Texas, USA.
Ann Rheum Dis. 2019 Nov;78(11):1583-1591. doi: 10.1136/annrheumdis-2019-215208. Epub 2019 Aug 22.
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.
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.
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.
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.
大量证据表明，I 型干扰素信号（或 I 型 IFN 特征）的失调在系统性硬化症（SSc）的发病机制中起作用。干扰素调节因子 7（IRF7）已被认为是 I 型 IFN 信号的主要调节因子。本研究的目的是阐明 IRF7 在皮肤纤维化和 SSc 发病机制中的作用。
研究了 SSc 和健康对照皮肤活检组织，以确定 IRF7 的表达和激活情况。在博来霉素诱导和 TSK/+小鼠模型中使用 IRF7 敲除（KO）小鼠研究了 IRF7 在纤维化中的作用。对来自 SSc 患者和健康对照的真皮成纤维细胞进行了体外实验。
与未受影响的匹配对照相比，IRF7 在 SSc 皮肤组织和离体 SSc 真皮成纤维细胞中的表达明显上调和激活。此外，IFN-α可刺激真皮成纤维细胞中的 IRF7 表达。重要的是，IRF7 与转化生长因子（TGF）-β信号的关键介质 Smad3 共免疫沉淀，IRF7 敲低可减少 SSc 成纤维细胞中的促纤维化因子。与野生型小鼠相比，IRF7 KO 小鼠在博来霉素反应中表现出皮肤纤维化和炎症减轻。具体而言，IRF7 KO 小鼠皮肤组织中的羟脯氨酸含量、真皮厚度以及 Col1a2、ACTA2 和白细胞介素 6mRNA 水平明显降低。此外，在 TSK/+小鼠中，IRF7 KO 可降低羟脯氨酸含量、皮下真皮厚度、Col1a2 mRNA 以及α-平滑肌肌动蛋白和纤维连接蛋白的表达。
IRF7 在 SSc 皮肤中上调，与 Smad3 相互作用并增强 TGF-β介导的纤维化，因此可能是 SSc 的一个有前途的治疗靶点。
