Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage.
Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage.
复制标题
小胶质细胞 Hv1 质子通道通过氧化损伤促进铜宗诱导的脱髓鞘。
DOI：
10.1111/jnc.13242
复制
发表时间：
2015-10
影响因子：
4.7
通讯作者：
Wu LJ
中科院分区：
文献类型：
--
作者：
Liu J;Tian D;Murugan M;Eyo UB;Dreyfus CF;Wang W;Wu LJ
在包括小胶质细胞在内的炎性细胞中，NADPH氧化酶（NOX）依赖性活性氧（ROS）的产生在多发性硬化（MS）的脱髓鞘和自由基介导的组织损伤中起重要作用。然而，小胶质细胞ROS产生和脱髓鞘的机制仍然很大程度上未知。电压门控质子通道Hv 1在小胶质细胞中选择性表达，并且是脑中NOX依赖性ROS产生所需的。在本研究中，我们试图确定小胶质细胞Hv 1质子通道的作用，在小鼠模型的cuprizone诱导的脱髓鞘，MS的模型。暴露后，野生型小鼠呈现明显的脱髓鞘，髓鞘碱性蛋白表达减少，成熟少突胶质细胞的损失，和受损的运动协调在一个正常的饮食小鼠相比。然而，与野生型小鼠相比，缺乏Hv 1（Hv 1 −/−）的小鼠部分免受脱髓鞘和运动缺陷的影响。在铜腙诱导的脱髓鞘中，Hv 1 −/−小鼠的这些获救表型伴随着ROS产生减少、小胶质细胞活化改善、少突胶质细胞祖细胞（NG 2）增殖增加和成熟少突胶质细胞数量增加。这些结果表明，Hv 1质子通道所需的铜腙诱导的小胶质细胞氧化损伤和随后的脱髓鞘。我们的研究表明小胶质细胞Hv 1质子通道是MS发病机制中控制NOX依赖性ROS产生的独特靶点。
NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) production in inflammatory cells including microglia plays an important role in demyelination and free radical-mediated tissue injury in multiple sclerosis (MS). However, the mechanism underlying microglial ROS production and demyelination remains largely unknown. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent ROS generation in the brain. In the present study, we sought to determine the role of microglial Hv1 proton channels in a mouse model of cuprizone-induced demyelination, a model for MS. Following cuprizone exposure, wild-type mice presented obvious demyelination, decreased myelin basic protein expression, loss of mature oligodendrocytes, and impaired motor coordination in comparison to mice on a normal chow diet. However, mice lacking Hv1 (Hv1−/−) are partially protected from demyelination and motor deficits compared with those in wild-type mice. These rescued phenotypes in Hv1−/− mice in cuprizone-induced demyelination is accompanied by reduced ROS production, ameliorated microglial activation, increased oligodendrocyte progenitor cell (NG2) proliferation, and increased number of mature oligodendrocytes. These results demonstrate that the Hv1 proton channel is required for cuprizone-induced microglial oxidative damage and subsequent demyelination. Our study suggests that the microglial Hv1 proton channel is a unique target for controlling NOX-dependent ROS production in the pathogenesis of MS.