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Knockout of microglial Hv1 proton channel reduces neurotoxic A1 astrocytes and neuronal damage via the ROS/STAT3 pathway after spinal cord injury

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收录情况： ◇ SCIE

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单位： [1]Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [2]Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China.

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关键词： A1/A2 astrocytes microglia reactive oxygen species spinal cord injury voltage-gated proton channel Hv1

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Spinal cord injury (SCI) causes severe functional deficits and neuronal damage, accompanied by intense glial activation. The voltage-gated proton channel Hv1, selectively expressed on microglia, is associated with SCI progression. However, the effect of Hv1 on the phenotypes and functions of reactive astrocytes after SCI remains unclear. Here, we combined Hv1 knockout (Hv1-/- ) mice and T10 spinal cord contusion to investigate the effects of microglial Hv1 on SCI pathophysiology and the phenotypes and functions of reactive astrocytes. After SCI, astrocytes proliferated and activated in the peri-injury area and exhibited an A1-dominant phenotype. Hv1 knockout reduced neurotoxic A1 astrocytes and shifted the dominant phenotype of reactive astrocytes from A1 to A2, enhancing synaptogenesis promotion, phagocytosis, and neurotrophy of astrocytes. Moreover, synaptic and axonal remodeling as well as motor recovery after SCI benefited from the improved astrocytic functions of Hv1 knockout. Furthermore, exogenous and endogenous reactive oxygen species (ROS) in astrocytes after SCI were reduced by Hv1 knockout. Our in vitro results showed that inhibition of ROS reduced the neurotoxic A1 phenotype in primary astrocytes via the STAT3 pathway. Similar to the effect of Hv1 knockout, the application of the ROS scavenger N-acetylcysteine reduced SCI-induced neurotoxic A1 astrocytes in vivo. Based on the in vivo and vitro results, we elucidated that microglial Hv1 knockout promotes synaptic and axonal remodeling in SCI mice by decreasing neurotoxic A1 astrocytes and increasing neuroprotective A2 astrocytes via the ROS/STAT3 pathway. Therefore, the Hv1 proton channel is a promising target for the treatment of SCI.© 2023 Wiley Periodicals LLC.

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出版当年[2022]版：

大类 | 1 区

医学

小类 | 2 区神经科学

最新[2025]版：

大类 | 2 区医学

小类 | 2 区神经科学

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出版当年[2021]版：

Q1 NEUROSCIENCES

最新[2023]版：

Q1 NEUROSCIENCES

影响因子： 5.4 最新[2023版] 6.6 最新五年平均 8.073 出版当年[2021版] 7.956 出版当年五年平均 7.452 出版前一年[2020版] 6.2 出版后一年[2022版]

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第一作者单位： [1]Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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通讯作者：

通讯机构： [1]Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [2]Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China. [*1]Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China

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