Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease
Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease
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DOI：
10.1007/s12035-016-0249-9
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发表时间：
2017-12-01
影响因子：
5.1
通讯作者：
Peng, Yu-Ping
中科院分区：
文献类型：
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作者：
Liu, Zhan;Huang, Yan;Peng, Yu-Ping
辅助性T（Th）17细胞是CD 4（+）T淋巴细胞的一个亚群，具有强烈的促炎性，在许多炎症性疾病的发病机制中起重要作用。然而，参与的Th 17细胞在帕金森氏病（PD），其特征在于在黑质纹状体系统中的多巴胺能（DA能）神经元的进行性变性是不清楚的。在此，我们旨在证明Th 17细胞浸润到脑实质中，并在1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）或1-甲基-4-苯基吡啶（MPP+）诱导的PD模型中诱导神经炎症和DA能神经元死亡。通过经升主动脉注入血液循环的FITC标记的白蛋白的信号来评估黑质（SN）中的血脑屏障（BBB）破坏。应用活细胞成像系统观察Th 17细胞与神经元的直接接触，分别用白细胞功能相关抗原（LFA）-1和细胞间粘附分子（ICAM）-1对Th 17细胞进行染色。Th 17细胞侵入黑质区，破坏了黑质区的血脑屏障。在MPP+处理的腹侧中脑（VM）细胞培养物中，Th 17细胞加剧DA能神经元损失和促炎/神经营养因子紊乱。动态捕获LFA-1染色的Th 17细胞与ICAM-1染色的VM神经元的直接接触。用中和抗体阻断Th 17细胞中的LFA-1或阻断VM神经元中的ICAM-1均能消除Th 17诱导的DA能神经元死亡。这些结果证实了Th 17细胞通过受损的BBB浸润到PD小鼠的脑实质中，并通过促进胶质细胞活化以及重要地通过依赖于LFA-1/ICAM-1相互作用的对神经元的直接损伤来发挥神经毒性性质。
T helper (Th)17 cells, a subset of CD4(+) T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP+)-induced PD models. Blood-brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP+-treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.