JCV agnoprotein-induced reduction in CXCL5/LIX secretion by oligodendrocytes is associated with activation of apoptotic signaling in neurons.
JCV agnoprotein-induced reduction in CXCL5/LIX secretion by oligodendrocytes is associated with activation of apoptotic signaling in neurons.
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DOI：
10.1002/jcp.23065
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发表时间：
2012-08
影响因子：
5.6
通讯作者：
Darbinyan, Armine
中科院分区：
文献类型：
--
作者：
Merabova, Nana;Kaminski, Rafal;Krynska, Barbara;Amini, Shohreh;Khalili, Kamel;Darbinyan, Armine
在人类神经系统疾病中发现影响少突胶质细胞的进行性神经元/轴突变性，有力地支持了少突胶质细胞在保护轴突功能和促进神经元存活方面不可或缺的作用。中枢神经系统的影像和病理研究表明，进行性多灶性白质脑病(PML)存在神经轴突损伤，PML是一种中枢神经系统脱髓鞘疾病，其原因是在致病的嗜神经多瘤病毒JC复制时，少突胶质细胞被破坏。在这里，我们研究了参与少突胶质细胞和神经元之间通讯的细胞外因素。用表达JCV蛋白的CG4少突胶质细胞的条件培养液(CM)培养皮质神经元表明，CXCL5/lix是一种与人CXCL5/ENA78和CXCL6/GCP-2趋化因子密切相关的趋化因子，对神经细胞的生存是必不可少的。我们发现，在CM中，CXC5/lix的表达水平比对照细胞低。我们还证明了CG4 GFP-Agno细胞中CXCL5/lix的表达减少触发了皮质神经元中的一系列信号事件。对丝裂原活化蛋白激酶(MAPK)和糖原合成酶激酶(GSK3)通路的分析表明，它们参与了CXCL5/Lix信号缺失引起的神经细胞凋亡的机制。这些数据表明，在PML病变的发病机制中，寡突胶质细胞诱导的趋化因子产生的失调可能是神经元/轴突损伤的原因。
An indispensable role for oligodendrocytes in the protection of axon function and promotion of neuronal survival is strongly supported by the finding of progressive neuron/axon degeneration in human neurological diseases that affect oligodendrocytes. Imaging and pathological studies of the CNS have shown the presence of neuroaxonal injury in progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the CNS, resulting from destruction of oligodendrocytes upon productive replication of the pathogenic neurotropic polyomavirus JC. Here, we examined the extracellular factors involved in communication between oligodendrocytes and neurons. Culturing cortical neurons with conditioned medium (CM) from rat CG4 oligodendrocytic cells that express the JCV agnoprotein showed that CXCL5/LIX, which is a chemokine closely related to the human CXCL5/ENA78 and CXCL6/GCP-2 chemokines, is essential for neuronal cell survival. We found that in CM from agnoprotein-producing CG-4 cells level of CXC5/LIX is decreased compared to control cells. We also demonstrated that a reduced expression of CXCL5/LIX by CG4 GFP-Agno cells triggered a cascade of signaling events in cortical neurons. Analysis of mitogen-activated protein kinases (MAPK) and glycogen synthase kinase (GSK3) pathways showed that they are involved in mechanisms of neuronal apoptosis in response to the depletion of CXCL5/LIX signaling. These data suggest that agnoprotein-induced dysregulation of chemokine production by oligodendrocytes may contribute to neuronal/axonal injury in the pathogenesis of PML lesions.
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