α-突触核蛋白通过促进帕金森病中 RORC 转录诱导 Th17 分化，并损害 Treg 的功能和稳定性。

α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease.

机构信息

Department of Neurology, Tongji Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan 430000, China.

Department of Rheumatology and Immunology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Center for Biomedical Research, Tongji Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, China.

出版信息

Brain Behav Immun. 2023 Feb;108:32-44. doi: 10.1016/j.bbi.2022.10.023. Epub 2022 Nov 4.

DOI:10.1016/j.bbi.2022.10.023

PMID:36343753

Abstract

BACKGROUND

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons (DA) and the accumulation of Lewy body deposits composed of alpha-Synuclein (α-Syn), which act as antigenic epitopes to drive cytotoxic T-cell responses in PD. Increased T helper 17 (Th17) cells and dysfunctional regulatory T cells (Tregs) have been reported to be associated with the loss of DA in PD. However, the mechanism underlying the Th17/Treg imbalance remains unknown.

METHODS

Here, we examined the percentage of Th17 cells, the percentage of Tregs and the α-Syn level and analysed their correlations in the peripheral blood of PD patients and in the substantia nigra pars compacta (SNpc) and spleen of MPTP-treated mice and A53 transgenic mice. We assessed the effect of α-Syn on the stability and function of Tregs and the differentiation of Th17 cells and evaluated the role of retinoid-related orphan nuclear receptor (RORγt) upregulation in α-Syn stimulation in vivo and in vitro.

RESULTS

We found that the α-Syn level and severity of motor symptoms were positively correlated with the increase in Th17 cells and decrease in Tregs in PD patients. Moreover, α-Syn stimulation led to the loss of Forkhead box protein P3 (FOXP3) expression in Tregs, accompanied by the acquisition of IL-17A expression. Increased Th17 differentiation was detected upon α-Syn stimulation when naïve CD4 T cells were cultured under Th17-polarizing conditions. Mechanistically, α-Syn promotes the transcription of RORC, encoding RORγt, in Tregs and Th17 cells, leading to increased Th17 differentiation and loss of Treg function. Intriguingly, the increase in Th17 cells, decrease in Tregs and apoptosis of DA were suppressed by a RORγt inhibitor (GSK805) in MPTP-treated mice.

CONCLUSION

Together, our data suggest that α-Syn promotes the transcription of RORC in circulating CD4 T cells, including Tregs and Th17 cells, to impair the stability of Tregs and promote the differentiation of Th17 cells in PD. Inhibition of RORγt attenuated the apoptosis of DA and alleviated the increase in Th17 cells and decrease in Tregs in PD.

摘要

背景

帕金森病（PD）的特征是多巴胺能神经元（DA）的丧失和由α-突触核蛋白（α-Syn）组成的路易体沉积物的积累，α-Syn 作为抗原表位，在 PD 中驱动细胞毒性 T 细胞反应。据报道，辅助性 T 细胞 17（Th17）细胞增加和调节性 T 细胞（Tregs）功能障碍与 PD 中 DA 的丧失有关。然而，Th17/Treg 失衡的机制尚不清楚。

方法

在这里，我们检查了 PD 患者外周血、MPTP 处理的小鼠和 A53 转基因小鼠的黑质致密部（SNpc）和脾脏中 Th17 细胞的百分比、Tregs 的百分比以及 α-Syn 水平，并分析了它们之间的相关性。我们评估了 α-Syn 对 Tregs 的稳定性和功能以及 Th17 细胞分化的影响，并评估了视黄酸相关孤儿核受体（RORγt）上调在体内和体外 α-Syn 刺激中的作用。

结果

我们发现，α-Syn 水平和运动症状的严重程度与 PD 患者 Th17 细胞增加和 Tregs 减少呈正相关。此外，α-Syn 刺激导致 Tregs 中叉头框蛋白 P3（FOXP3）表达丧失，同时获得 IL-17A 表达。当在 Th17 极化条件下培养幼稚 CD4 T 细胞时，发现 α-Syn 刺激会增加 Th17 分化。在机制上，α-Syn 在 Tregs 和 Th17 细胞中促进编码 RORγt 的 RORC 的转录，导致 Th17 分化增加和 Treg 功能丧失。有趣的是，RORγt 抑制剂（GSK805）在 MPTP 处理的小鼠中抑制了 Th17 细胞的增加、Tregs 的减少和 DA 的凋亡。