Soluble Tumor Necrosis Factor Receptor 1 Released by Skin-Derived Mesenchymal Stem Cells Is Critical for Inhibiting Th17 Cell Differentiation

Author:

Ke Fang1,Zhang Lingyun1,Liu Zhaoyuan1,Yan Sha1,Xu Zhenyao1,Bai Jing1,Zhu Huiyuan1,Lou Fangzhou1,Cai Wei1,Sun Yang1,Gao Yuanyuan1,Wang Hong1,Wang Honglin12

Affiliation:

1. Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China

2. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China

Abstract

Abstract 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.

Funder

973 Program and National Natural Science Foundation of China

Leading Academic Discipline Project of the Shanghai Municipal Education Commission

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,General Medicine

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