Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital Boston and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
Nat Neurosci. 2012 Mar 4;15(4):565-73. doi: 10.1038/nn.3059.
Phagocytic cell NADPH oxidase (NOX) generates reactive oxygen species (ROS) as part of innate immunity. Unfortunately, ischemia can also induce this pathway and inflict damage on native cells. The voltage-gated proton channel Hv1 enables NOX function by compensating cellular loss of electrons with protons. Accordingly, we investigated whether NOX-mediated brain damage in stroke can be inhibited by suppression of Hv1. We found that mouse and human brain microglia, but not neurons or astrocytes, expressed large Hv1-mediated currents. Hv1 was required for NOX-dependent ROS generation in brain microglia in situ and in vivo. Mice lacking Hv1 were protected from NOX-mediated neuronal death and brain damage 24 h after stroke. These results indicate that Hv1-dependent ROS production is responsible for a substantial fraction of brain damage at early time points after ischemic stroke and provide a rationale for Hv1 as a therapeutic target for the treatment of ischemic stroke.
吞噬细胞 NADPH 氧化酶（NOX）作为先天免疫的一部分产生活性氧（ROS）。不幸的是，缺血也可以诱导这一途径，并对固有细胞造成损伤。电压门控质子通道 Hv1 通过用质子补偿细胞中电子的损失来使 NOX 发挥功能。因此，我们研究了中风中 NOX 介导的脑损伤是否可以通过抑制 Hv1 来抑制。我们发现，小鼠和人脑小胶质细胞，但不是神经元或星形胶质细胞，表达大的 Hv1 介导的电流。Hv1 是脑小胶质细胞原位和体内 NOX 依赖性 ROS 生成所必需的。缺乏 Hv1 的小鼠在中风后 24 小时免受 NOX 介导的神经元死亡和脑损伤的影响。这些结果表明，Hv1 依赖性 ROS 产生是缺血性中风后早期大量脑损伤的原因，并为 Hv1 作为治疗缺血性中风的治疗靶点提供了依据。
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