Mount Matthew P, Lira Arman, Grimes David, Smith Patrice D, Faucher Sylvie, Slack Ruth, Anisman Hymie, Hayley Shawn, Park David S
Ottawa Health Research Institute, Neuroscience Group, Ottawa, Ontario, Canada K1H 8M5.
J Neurosci. 2007 Mar 21;27(12):3328-37. doi: 10.1523/JNEUROSCI.5321-06.2007.
Growing evidence implicates microglia in the loss of dopaminergic neurons in Parkinson's disease (PD). However, factors mediating microglial activation in PD are poorly understood. Proinflammatory cytokines, such as interferon-gamma (IFN-gamma), orchestrate the actions of microglia. We report here that PD patients express significantly elevated levels of IFN-gamma in their blood plasma. After this initial finding, we found that IFN-gamma-deficient mice displayed attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced substantia nigra pars compacta dopaminergic cell loss along with reduced loss of striatal tyrosine hydroxylase and dopamine transporter fiber density. MPTP-induced depletion of striatal dopamine and its metabolite DOPAC (3,4-dihydroxyphenylacetic acid), as well as deltaFosB, a marker of postsynaptic dysfunction, were also attenuated in these knock-out mice. Consistent with the role for IFN-gamma in microglial activation, MPTP-induced morphological activation of microglia was abrogated compared with wild-type mice. To examine more mechanistically the role of IFN-gamma in microglial activation, we evaluated the interactions between microglia and dopaminergic neurons in an in vitro mixed microglia/midbrain neuron rotenone-induced death paradigm. In this in vitro paradigm, dopaminergic neurons are selectively damaged by rotenone. Exogenous IFN-gamma ligand alone and without rotenone resulted in dopaminergic cell loss, but only in the presence of microglia. The addition of an IFN-gamma neutralizing antibody attenuated neuronal loss as a result of rotenone treatment. The presence of only wild-type microglia and not those deficient in IFN-gamma receptor elicited significant dopaminergic cell loss when exposed to rotenone. Neurons deficient in IFN-gamma receptor, however, did not display increased resistance to death. Finally, levels of IFN-gamma message increased in microglia in response to rotenone. Together, these data suggest that IFN-gamma participates in death of dopaminergic neurons by regulating microglial activity.
越来越多的证据表明，小胶质细胞与帕金森病（PD）中多巴胺能神经元的丧失有关。然而，介导PD中小胶质细胞活化的因素却知之甚少。促炎细胞因子，如干扰素-γ（IFN-γ），可协调小胶质细胞的作用。我们在此报告，PD患者血浆中IFN-γ水平显著升高。在这一初步发现之后，我们发现IFN-γ缺陷小鼠表现出1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的黑质致密部多巴胺能细胞损失减轻，同时纹状体酪氨酸羟化酶和多巴胺转运体纤维密度的损失也减少。在这些基因敲除小鼠中，MPTP诱导的纹状体多巴胺及其代谢产物3,4-二羟基苯乙酸（DOPAC）的耗竭，以及突触后功能障碍的标志物deltaFosB也有所减轻。与IFN-γ在小胶质细胞活化中的作用一致，与野生型小鼠相比，MPTP诱导的小胶质细胞形态活化被消除。为了更深入地研究IFN-γ在小胶质细胞活化中的作用机制，我们在体外混合小胶质细胞/中脑神经元鱼藤酮诱导的死亡模型中评估了小胶质细胞与多巴胺能神经元之间的相互作用。在这个体外模型中，多巴胺能神经元被鱼藤酮选择性损伤。单独的外源性IFN-γ配体且无鱼藤酮时会导致多巴胺能细胞损失，但仅在有小胶质细胞存在的情况下。添加IFN-γ中和抗体可减轻鱼藤酮处理导致的神经元损失。当暴露于鱼藤酮时，仅野生型小胶质细胞而非缺乏IFN-γ受体的小胶质细胞会引起显著的多巴胺能细胞损失。然而，缺乏IFN-γ受体的神经元对死亡的抵抗力并未增加。最后，小胶质细胞中IFN-γ信息水平因鱼藤酮而升高。总之，这些数据表明IFN-γ通过调节小胶质细胞活性参与多巴胺能神经元的死亡。
