Soluble Tumor Necrosis Factor Receptor 1 Released by Skin-Derived Mesenchymal Stem Cells Is Critical for Inhibiting Th17 Cell Differentiation
Soluble Tumor Necrosis Factor Receptor 1 Released by Skin-Derived Mesenchymal Stem Cells Is Critical for Inhibiting Th17 Cell Differentiation
复制标题
皮肤源性间充质干细胞释放的可溶性肿瘤坏死因子受体1对于抑制Th17细胞分化至关重要
DOI：
10.5966/sctm.2015-0179
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发表时间：
2016-03-01
影响因子：
6
通讯作者：
Wang, Honglin
中科院分区：
文献类型：
--
作者：
Ke, Fang;Zhang, Lingyun;Wang, Honglin
T辅助17 （Th17）细胞在多发性硬化症（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）中发挥重要作用。细胞因子转化生长因子β 1和白细胞介素-6可诱导Th17细胞从幼稚T细胞向体外分化。然而，是否有其他调控因子控制Th17细胞的分化尚不清楚。间充质干细胞（MSCs）已成为抑制Th17细胞分化和自身免疫疾病的有希望的候选者。尽管有几个分子与MSCs的免疫调节功能有关，但许多其他关键的MSCs分泌的调节因子参与抑制Th17细胞极化的定义不明确。在这项研究中，我们证明了腹腔注射皮肤来源的MSCs （S-MSCs）可以显著改善小鼠EAE的发展。我们发现促炎细胞因子肿瘤坏死因子(TNF)- α是MS和EAE病理生理的关键介质，能够促进Th17细胞分化。此外，在炎症条件下，我们证明S-MSCs产生大量可溶性TNF受体1 (sTNFR1)，其结合TNF- α并拮抗其功能。在S-MSCs中敲低sTNFR1可降低其在体内和体外对Th17细胞分化的抑制作用。因此，我们的数据确定了sTNFR1及其靶标tnf - α是Th17细胞分化的关键调节因子，这表明MSC治疗Th17介导的自身免疫性疾病的机制以前未被认识到。
T helper 17 (Th17) cells play an important role in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Th17 cell differentiation from naive T cells can be induced in vitro by the cytokines transforming growth factor beta 1 and interleukin-6. However, it remains unclear whether other regulatory factors control the differentiation of Th17 cells. Mesenchymal stem cells (MSCs) have emerged as a promising candidate for inhibiting Th17 cell differentiation and auto immune diseases. Despite the fact that several molecules have been linked to the immunomodulatory function of MSCs, many other key MSC-secreted regulators that are involved in inhibiting Th17 cell polarization are ill-defined. In this study, we demonstrated that the intraperitoneal administration of skin-derived MSCs (S-MSCs) substantially ameliorated the development of EAE in mice. We found that the proinflammatory cytokine tumor necrosis factor (TNF)-alpha, a key mediator in the pathophysiology of MS and EAE, was capable of promoting Th17 cell differentiation. Moreover, under inflammatory conditions, we demonstrated that S-MSCs produced high amounts of soluble TNF receptor 1 (sTNFR1), which binds TNF-alpha and antagonizes its function. Knockdown of sTNFR1 in S-MSCs decreased their inhibitory effect on Th17 cell differentiation ex vivo and in vivo. Thus, our data identified sTNFR1 and its target TNF-alpha as critical regulators for Th17 cell differentiation, suggesting a previously unrecognized mechanism for MSC therapy in Th17-mediated autoimmune diseases.