Deficiency in the voltage-gated proton channel Hv1 increases M2 polarization of microglia and attenuates brain damage from photothrombotic ischemic stroke.
Deficiency in the voltage-gated proton channel Hv1 increases M2 polarization of microglia and attenuates brain damage from photothrombotic ischemic stroke.
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DOI：
10.1111/jnc.13751
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发表时间：
2016-10
影响因子：
4.7
通讯作者：
Liu JL
中科院分区：
文献类型：
--
作者：
Tian DS;Li CY;Qin C;Murugan M;Wu LJ;Liu JL
小胶质细胞在脑缺血时被激活，并依赖于小胶质细胞的极化发挥促炎或抗炎作用。小胶质细胞中NADPH氧化酶(NOX)依赖的活性氧(ROS)的产生在缺血性卒中后神经元损伤中起重要作用。近来，NOX和ROS一直被报道参与小胶质细胞的激活和极化；NOX2抑制或抑制ROS的产生被证明在卒中后将小胶质细胞的极化从M1状态转变为M2状态。电压门控质子通道Hv1选择性地在小胶质细胞中表达，是大脑中NOX依赖的ROS产生所必需的。然而，Hv1质子通道对脑缺血后小胶质细胞M1/M2极化状态的影响尚不清楚。在本研究中，我们利用小鼠光凝模型研究了小胶质细胞Hv1质子通道在调节小胶质细胞M1/M2极化中的作用。在光栓性缺血性卒中后，野生型小鼠表现出明显的脑梗塞、神经元损伤和运动协调能力受损。然而，与野生型小鼠相比，缺乏Hv1(Hv1−/−)的小鼠部分免受脑损伤和运动障碍的影响。这些被挽救的表型在缺血性卒中的Hv1−/−小鼠中伴随着ROS产生的减少，使小胶质细胞的极化从M1状态转移到M2状态。在原代培养的小胶质细胞中，HV1缺乏也改变了M1/M2极化。我们的研究表明，小胶质细胞Hv1质子通道是调节小胶质细胞M1/M2极化的独特靶点。
Microglia become activated during cerebral ischemia and exert pro-inflammatory or anti-inflammatory role dependent of microglial polarization. NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) production in microglia plays an important role in neuronal damage after ischemic stroke. Recently, NOX and ROS are consistently reported to participate in the microglial activation and polarization; NOX2 inhibition or suppression of ROS production are shown to shift the microglial polarization from M1 toward M2 state after stroke. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent ROS generation in the brain. However, the effect of Hv1 proton channel on microglial M1/M2 polarization state after cerebral ischemia remains unknown. In the present study, we investigated the role of microglial Hv1 proton channel in modulating microglial M1/M2 polarization during the pathogenesis of ischemic cerebral injury using a mouse model of photothrombosis. Following photothrombotic ischemic stroke, wild-type mice presented obvious brain infarct, neuronal damage and impaired motor coordination. However, mice lacking Hv1 (Hv1−/−) were partially protected from brain damage and motor deficits compared to wild-type mice. These rescued phenotypes in Hv1 −/−mice in ischemic stroke is accompanied by reduced ROS production, shifted the microglial polarization from M1 to M2 state. Hv1 deficiency was also found to shift the M1/M2 polarization in primary cultured microglia. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke.
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影响因子：
9.3
作者：
Cherry JD;Olschowka JA;O'Banion MK
通讯作者：
O'Banion MK
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。
影响因子：
4.7
作者：
Liu J;Tian D;Murugan M;Eyo UB;Dreyfus CF;Wang W;Wu LJ
通讯作者：
Wu LJ
影响因子：
4.7
作者：
Choi SH;Aid S;Kim HW;Jackson SH;Bosetti F
通讯作者：
Bosetti F
DOI：
10.1016/j.bbrc.2009.12.114
发表时间：
2010-01-15
影响因子：
3.1
作者：
Hur, Jinyoung;Lee, Pyeongjae;Cho, Young-Wuk
通讯作者：
Cho, Young-Wuk
影响因子：
6.1
作者：
Kahles, Timo;Kohnen, Andreas;Brandes, Ralf P.
通讯作者：
Brandes, Ralf P.