System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes
System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes
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DOI：
10.4049/jimmunol.178.10.6549
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发表时间：
2007-05-15
影响因子：
4.4
通讯作者：
Matute, Carlos
中科院分区：
文献类型：
--
作者：
Domercq, Maria;Sanchez-Gomez, Maria Victoria;Matute, Carlos
细胞外谷氨酸水平升高可引起兴奋毒性少突胶质细胞死亡，并在多发性硬化症和脑室周围白质软化等白质疾病中导致进行性少突胶质细胞丢失和脱髓鞘。然而，在这种情况下谷氨酸稳态改变的机制仍然是难以捉摸的。我们在这里表明，小胶质细胞，在他们的激活状态，损害谷氨酸稳态培养少突胶质细胞。激活的和静止的小胶质细胞都通过胱氨酸-谷氨酸反转运系统x(c)（-）释放谷氨酸。此外，激活的小胶质细胞阻断少突胶质细胞中的谷氨酸转运蛋白，导致细胞外谷氨酸的净增加和随后的少突胶质细胞死亡。阻断α -氨基-3-羟基-5-甲基-4-异恶唑烯丙酸(AMPA)/海因酸盐受体或系统x(c)（-）反转运蛋白可防止暴露于lps激活的混合胶质细胞中产生的少突胶质细胞损伤。在全载大鼠视神经中，LPS暴露产生广泛的少突胶质细胞损伤，AMPA/kainate受体阻断可预防这种损伤，并通过系统x(c)（-）反转运蛋白阻断大大减轻这种损伤。细胞死亡的典型特征是线粒体的肿胀和破坏，这一特征在密切相关的轴突线粒体中没有发现。我们的研究结果揭示了一种新的机制，反应性小胶质细胞可以帮助改变谷氨酸稳态和白质疾病的发病机制。免疫学杂志，2007,18(2):649 - 656。
Elevated levels of extracellular glutamate cause excitotoxic oligodendrocyte cell death and contribute to progressive oligodendrocyte loss and demyelination in white matter disorders such as multiple sclerosis and periventricular leukomalacia. However, the mechanism by which glutamate homeostasis is altered in such conditions remains elusive. We show here that microglial cells, in their activated state, compromise glutamate homeostasis in cultured oligodendrocytes. Both activated and resting microglial cells release glutamate by the cystine-glutamate antiporter system x(c)(-). In addition, activated microglial cells act to block glutamate transporters in oligodendrocytes, leading to a net increase in extracellular glutamate and subsequent oligodendrocyte death. The blocking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors or the system x(c)(-) antiporter prevented the oligodendrocyte injury produced by exposure to LPS-activated microglial cells in mixed glial cultures. In a whole-mount rat optic nerve, LPS exposure produced wide-spread oligodendrocyte injury that was prevented by AMPA/kainate receptor block and greatly reduced by a system x(c)(-) antiporter block. The cell death was typified by swelling and disruption of mitochondria, a feature that was not found in closely associated axonal mitochondria. Our results reveal a novel mechanism by which reactive microglia can contribute to altering glutamate homeostasis and to the pathogenesis of white matter disorders. The Journal of Immunology, 2007, 178: 6549-6556.