Loss of Smad7 Promotes Inflammation in Rheumatoid Arthritis.
Loss of Smad7 Promotes Inflammation in Rheumatoid Arthritis.
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Smad7 缺失会促进类风湿性关节炎的炎症
DOI：
10.3389/fimmu.2018.02537
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发表时间：
2018
影响因子：
7.3
通讯作者：
Wang QW
中科院分区：
文献类型：
--
作者：
Zhou G;Sun X;Qin Q;Lv J;Cai Y;Wang M;Mu R;Lan HY;Wang QW
目的：Smad7是一种抑制性Smad，在多种炎症性疾病中发挥保护作用。然而，Smad7 在类风湿性关节炎 (RA) 中的作用仍未得到探索，本研究对此进行了研究。方法：检测 RA 患者滑膜组织中 TGF-β/Smad 信号传导的激活情况。 Smad7 在 RA 中的功能作用和机制是在 Smad7 野生型 (WT) 和敲除 (KO) CD-1 小鼠（一种对自身免疫性关节炎诱导具有抗性的品系）的胶原诱导关节炎 (CIA) 小鼠模型中确定的。结果：RA患者滑膜组织中TGF-β/Smad3信号显着激活，这与Smad7的缺失以及Th17和Th1免疫反应的增强有关。在 Smad7 WT/KO CD-1 小鼠的 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 小鼠没有出现 CIA。令人惊讶的是，Smad7 缺陷的 CD-1 小鼠出现了严重的关节炎，包括严重的关节肿胀、滑膜增生、软骨损伤、CD3+ T 细胞和 F4/80+ 巨噬细胞大量浸润，以及促炎细胞因子 IL-1β、TNFα 和 MCP-1 的上调。进一结论：Smad7 缺陷会增加 CD-1 小鼠对自身免疫性关节炎的易感性。增强的 TGF-β/Smad3-IL-6 信号传导和 Th17 免疫反应可能是 Smad7 破坏导致 CD-1 小鼠自身免疫性关节炎的机制。
Objective: 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. Methods: 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. Results: 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. Conclusions: 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.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
4.6
作者：
Chen SY;Shiau AL;Wu CL;Wang CR
通讯作者：
Wang CR
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
4.8
作者：
Chang SH;Dong C
通讯作者：
Dong C
DOI：
10.1111/j.1440-1681.2011.05663.x
发表时间：
2012-08-01
影响因子：
2.9
作者：
Lan, Hui Yao
通讯作者：
Lan, Hui Yao