Department of Neurological Sciences, Rush University Medical Center, Chicago, USA.
Department of Neurological Sciences, Rush University Medical Center, Chicago, USA; Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, USA.
Neurobiol Dis. 2019 Dec;132:104575. doi: 10.1016/j.nbd.2019.104575. Epub 2019 Aug 22.
Although Parkinson's disease (PD) is a progressive neurodegenerative disease, the disease does not progress or persist in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, the most common animal model of PD. Recently, we have described that supplementation of regulated on activation, normal T cell expressed and secreted (RANTES), a chemokine known to drive infiltration of T cells, induces persistent nigrostriatal pathology in MPTP mouse model. However, which particular T cell subsets are recruited to the substantia nigra (SN) by RANTES is not known. Here, by adoptive transfer of different subset of T cells from tomato red transgenic mice to MPTP-intoxicated immunodeficient Rag1 mice, we describe that invasion of Th17 cells into the SN is stimulated by exogenous RANTES administration. On the other hand, RANTES supplementation remained unable to influence the infiltration of Th1 and Tregs into the SN of MPTP-insulted Rag1 mice. Accordingly, RANTES supplementation increased MPTP-induced TH cell loss in Rag1mice receiving Th17, but neither Th1 nor Tregs. RANTES-mediated aggravation of nigral TH neurons also paralleled with significant DA loss in striatum and locomotor deficits in MPTP-intoxicated Rag1 mice receiving Th17 cells. Finally, we demonstrate that levels of IL-17 (a Th17-specific cytokine) and RANTES are higher in serum of PD patients than age-matched controls and that RANTES positively correlated with IL-17 in serum of PD patients. Together, these results highlight the importance of RANTES-Th17 pathway in progressive dopaminergic neuronal loss and associated PD pathology.
尽管帕金森病（PD）是一种进行性神经退行性疾病，但在最常见的 PD 动物模型 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠模型中，疾病不会进展或持续存在。最近，我们描述了调节激活正常 T 细胞表达和分泌（RANTES）的补充，一种已知可驱动 T 细胞浸润的趋化因子，可诱导 MPTP 小鼠模型中持续性黑质纹状体病理学。然而，RANTES 招募到黑质（SN）的特定 T 细胞亚群尚不清楚。在这里，通过从番茄红素转基因小鼠向 MPTP 中毒免疫缺陷 Rag1 小鼠过继转移不同的 T 细胞亚群，我们描述了外源性 RANTES 给药刺激 Th17 细胞侵入 SN。另一方面，RANTES 补充仍然无法影响 Th1 和 Tregs 浸润 MPTP 损伤的 Rag1 小鼠的 SN。因此，RANTES 补充增加了 Rag1 小鼠中接受 Th17 的 MPTP 诱导的 TH 细胞丢失，但对 Th1 或 Tregs 没有影响。RANTES 介导的黑质 TH 神经元加重也与 Rag1 小鼠中接受 Th17 细胞的 MPTP 中毒的纹状体中 DA 丢失和运动缺陷平行。最后，我们证明 PD 患者血清中的 IL-17（一种 Th17 特异性细胞因子）和 RANTES 水平高于年龄匹配的对照，并且 PD 患者血清中的 RANTES 与 IL-17 呈正相关。总之，这些结果强调了 RANTES-Th17 途径在进行性多巴胺能神经元丢失和相关 PD 病理学中的重要性。
