Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China.
Department of Rheumatology and Immunology, Peking University People's Hospital, Peking, China.
Front Immunol. 2018 Nov 2;9:2537. doi: 10.3389/fimmu.2018.02537. eCollection 2018.
Smad7 is an inhibitory Smad and plays a protective role in many inflammatory diseases. However, the roles of Smad7 in rheumatoid arthritis (RA) remain unexplored, which were investigated in this study. The activation of TGF-β/Smad signaling was examined in synovial tissues of patients with RA. The functional roles and mechanisms of Smad7 in RA were determined in a mouse model of collagen-induced arthritis (CIA) in Smad7 wild-type (WT) and knockout (KO) CD-1 mice, a strain resistant to autoimmune arthritis induction. TGF-β/Smad3 signaling was markedly activated in synovial tissues of patients with RA, which was associated with the loss of Smad7, and enhanced Th17 and Th1 immune response. The potential roles of Smad7 in RA were further investigated in a mouse model of CIA in Smad7 WT/KO CD-1 mice. As expected, Smad7-WT CD-1 mice did not develop CIA. Surprisingly, CD-1 mice with Smad7 deficiency developed severe arthritis including severe joint swelling, synovial hyperplasia, cartilage damage, massive infiltration of CD3 T cells and F4/80 macrophages, and upregulation of proinflammatory cytokines IL-1β, TNFα, and MCP-1. Further studies revealed that enhanced arthritis in Smad7 KO CD-1 mice was associated with increased Th1, Th2 and, importantly, Th17 over the Treg immune response with overactive TGF-β/Smad3 and proinflammatory IL-6 signaling in the joint tissues. Smad7 deficiency increases the susceptibility to autoimmune arthritis in CD-1 mice. Enhanced TGF-β/Smad3-IL-6 signaling and Th17 immune response may be a mechanism through which disrupted Smad7 causes autoimmune arthritis in CD-1 mice.
Smad7 是一种抑制性 Smad，在许多炎症性疾病中发挥保护作用。然而，Smad7 在类风湿关节炎 (RA) 中的作用仍未得到探索，本研究对此进行了研究。检测了 RA 患者滑膜组织中 TGF-β/Smad 信号的激活情况。在 Smad7 野生型 (WT) 和敲除 (KO) CD-1 小鼠胶原诱导性关节炎 (CIA) 小鼠模型中，确定了 Smad7 在 RA 中的功能作用和机制，CD-1 小鼠对自身免疫性关节炎的诱导具有抗性。RA 患者滑膜组织中 TGF-β/Smad3 信号明显激活，这与 Smad7 的缺失有关，并增强了 Th17 和 Th1 免疫反应。在 Smad7 WT/KO CD-1 小鼠 CIA 小鼠模型中进一步研究了 Smad7 在 RA 中的潜在作用。正如预期的那样，Smad7-WT CD-1 小鼠未发展为 CIA。令人惊讶的是，Smad7 缺失的 CD-1 小鼠发生了严重的关节炎，包括严重的关节肿胀、滑膜增生、软骨损伤、大量 CD3 T 细胞和 F4/80 巨噬细胞浸润，以及促炎细胞因子 IL-1β、TNFα 和 MCP-1 的上调。进一步的研究表明，Smad7 KO CD-1 小鼠关节炎的增强与 Th1、Th2 和更重要的 Th17 反应的过度活跃有关，Treg 免疫反应与关节组织中 TGF-β/Smad3 和促炎 IL-6 信号的过度活跃有关。Smad7 缺失增加了 CD-1 小鼠自身免疫性关节炎的易感性。增强的 TGF-β/Smad3-IL-6 信号和 Th17 免疫反应可能是破坏 Smad7 导致 CD-1 小鼠自身免疫性关节炎的机制。
