Open AccessSoluble Tumor Necrosis Factor Receptor 1 Released by Skin‐Derived Mesenchymal Stem Cells Is Critical for Inhibiting Th17 Cell Differentiation
Author(s) -
Ke Fang,
Zhang Lingyun,
Liu Zhaoyuan,
Yan Sha,
Xu Zhenyao,
Bai Jing,
Zhu Huiyuan,
Lou Fangzhou,
Cai Wei,
Sun Yang,
Gao Yuanyuan,
Wang Hong,
Wang Honglin
Publication year - 2016
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.5966/sctm.2015-0179
Subject(s) - mesenchymal stem cell , microbiology and biotechnology , cancer research , tumor necrosis factor receptor , tumor necrosis factor alpha , stem cell , cellular differentiation , receptor , chemistry , biology , immunology , biochemistry , gene
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 naïve T cells can be induced in vitro by the cytokines transforming growth factor β1 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 autoimmune 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)‐α, 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‐α 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‐α as critical regulators for Th17 cell differentiation, suggesting a previously unrecognized mechanism for MSC therapy in Th17‐mediated autoimmune diseases. Significance This study showed that administration of skin‐derived mesenchymal stem cells (S‐MSCs) was able to alleviate the clinical score of experimental autoimmune encephalomyelitis by inhibiting the differentiation of T helper 17 (Th17) cells. Tumor necrosis factor (TNF)‐α is a critical cytokine for promoting Th17 cell differentiation. It was discovered that activated S‐MSCs produced high amount of soluble TNF receptor 1 (sTNFR1), which neutralized TNF‐α and inhibited Th17 cell polarization. The data identified S‐MSC‐secreted sTNFR1 and its target TNF‐α as essential regulators for Th17 cell differentiation and revealed a novel mechanism underlying MSC‐mediated immunomodulatory function in autoimmunity.