IRMB, INSERM, Université Montpellier, Montpellier, France.
Facultad de Medicina, Universidad de los Andes, Santiago, Chile.
Theranostics. 2018 Jan 1;8(3):846-859. doi: 10.7150/thno.21793. eCollection 2018.
Mesenchymal stem cells (MSC) are highly immunosuppressive cells able to reduce chronic inflammation through the active release of mediators. Recently, we showed that glucocorticoid-induced leucine zipper (Gilz) expression by MSC is involved in their therapeutic effect by promoting the generation of regulatory T cells. However, the mechanisms underlying this pivotal role of Gilz remain elusive. In this study, we have uncovered evidence that Gilz modulates the phenotype and function of Th1 and Th17 cells likely by upregulating the level of Activin A and NO secreted by MSC. Adoptive transfer experiments sustained this Gilz-dependent suppressive effect of MSC on Th1 and Th17 cell functions. In immunoregulatory MSC, obtained by priming with IFN-γ and TNF-α, Gilz was translocated to the nucleus and bound to the promoters of and to induce their expression. The increased expression of Activin A directly impacted on Th17 cells fate by repressing their differentiation program through the activation of Smad3/2 and enhancing IL-10 production. Our results reveal how Gilz controls and gene expression to ultimately assign immunoregulatory status to MSC able to repress the pathogenic Th17 cell differentiation program and uncover Activin A as a novel mediator of MSC in this process.
间质干细胞（MSC）是具有高度免疫抑制能力的细胞，能够通过主动释放介质来减轻慢性炎症。最近，我们发现 MSC 中糖皮质激素诱导的亮氨酸拉链（Gilz）的表达通过促进调节性 T 细胞的产生而参与其治疗效果。然而，Gilz 发挥这一关键作用的机制仍不清楚。在这项研究中，我们发现证据表明 Gilz 通过上调 MSC 分泌的 Activin A 和 NO 的水平来调节 Th1 和 Th17 细胞的表型和功能。过继转移实验证实了 MSC 对 Th1 和 Th17 细胞功能的这种依赖于 Gilz 的抑制作用。在通过 IFN-γ 和 TNF-α 预刺激获得的免疫调节 MSC 中，Gilz 易位到细胞核并与 和 的启动子结合，从而诱导它们的表达。Activin A 的表达增加直接通过激活 Smad3/2 抑制其分化程序来影响 Th17 细胞的命运，并通过增强 IL-10 的产生来增加其产生。我们的结果揭示了 Gilz 如何控制 和 的基因表达，从而最终赋予能够抑制致病性 Th17 细胞分化程序的 MSC 免疫调节状态，并揭示 Activin A 作为 MSC 在该过程中的一种新的介质。
