Proliferation of microglial cells induced by 1-methyl-4-phenylpyridinium in mesencephalic cultures results from an astrocyte-dependent mechanism: role of granulocyte macrophage colony-stimulating factor
Proliferation of microglial cells induced by 1-methyl-4-phenylpyridinium in mesencephalic cultures results from an astrocyte-dependent mechanism: role of granulocyte macrophage colony-stimulating factor
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DOI：
10.1111/j.1471-4159.2005.03416.x
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发表时间：
2005-11-01
影响因子：
4.7
通讯作者：
Michel, PP
中科院分区：
文献类型：
--
作者：
Henze, C;Hartmann, A;Michel, PP
有证据表明，炎症性小胶质细胞反应参与帕金森病和该疾病的动物模型中多巴胺能神经元死亡的病理生理学。然而，这一现象的特征仍然不完全。使用体外模型的神经元/神经胶质中脑文化，我们表明，多巴胺能神经毒素1-甲基-4-苯基吡啶（MPP+）刺激小胶质细胞增殖的浓度，选择性地减少DA神经元的生存。MPP+的促有丝分裂作用不仅仅是神经元细胞死亡的结果，因为毒素在不存在靶DA神经元的神经元/神经胶质皮质培养物的模型系统中产生相同的效果。与该观察结果一致，MPP+的增殖作用在无神经元的小胶质细胞/星形胶质细胞培养物中也可检测到。然而，当MPP+加入到纯的小胶质细胞培养物中时，它消失了，这表明星形胶质细胞在促有丝分裂机制中发挥了关键作用。因此，响应MPP+处理的小胶质细胞的增殖被粒细胞巨噬细胞集落刺激因子（GM-CSF）模拟，粒细胞巨噬细胞集落刺激因子（GM-CSF）是由星形胶质细胞产生的促炎细胞因子，并且被GM-CSF的中和抗体阻断。因此，我们得出结论，MPP+暴露后观察到的小胶质细胞反应取决于星形胶质细胞因子，例如GM-CSF，这一发现可能具有治疗意义。
There is evidence that an inflammatory microglial reaction participates in the pathophysiology of dopaminergic neuronal death in Parkinson's disease and in animal models of the disease. However, this phenomenon remains incompletely characterized. Using an in vitro model of neuronal/glial mesencephalic cultures, we show that the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) stimulates the proliferation of microglial cells at concentrations that selectively reduce the survival of DA neurones. The mitogenic action of MPP+ was not the mere consequence of neuronal cell demise as the toxin produced the same effect in a model system of neuronal/glial cortical cultures, where target DA neurones are absent. Consistent with this observation, the proliferative effect of MPP+ was also detectable in neurone-free microglial/astroglial cultures. It disappeared, however, when MPP+ was added to pure microglial cell cultures suggesting that astrocytes played a key role in the mitogenic mechanism. Accordingly, the proliferation of microglial cells in response to MPP+ treatment was mimicked by granulocyte macrophage colony-stimulating factor (GM-CSF), a proinflammatory cytokine produced by astrocytes and was blocked by a neutralizing antibody to GM-CSF. Thus, we conclude that the microglial reaction observed following MPP+ exposure depends on astrocytic factors, e.g. GM-CSF, a finding that may have therapeutic implications.