The voltage-gated proton channel Hv1 plays a detrimental role in contusion spinal cord injury via extracellular acidosis-mediated neuroinflammation.
The voltage-gated proton channel Hv1 plays a detrimental role in contusion spinal cord injury via extracellular acidosis-mediated neuroinflammation.
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DOI：
10.1016/j.bbi.2020.10.005
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Li Y;Ritzel RM;He J;Cao T;Sabirzhanov B;Li H;Liu S;Wu LJ;Wu J
组织酸中毒是创伤性脊髓损伤病理生理中一个重要的继发性损伤过程。迄今为止，还没有研究证实质子挤压在脊髓损伤病理性酸中毒中的作用。在本研究中，我们假设吞噬细胞特异性质子通道Hv1介导脊髓损伤后氢质子挤压，导致细胞外酸中毒增加和长期预后不良。利用成年雌性小鼠的脊髓损伤挫伤模型，我们发现在脊髓损伤后的第一周，组织pH值明显降低。酸中毒在损伤部位最为明显，但也延伸至颈腰椎近端。组织活性氧（ROS）水平和Hv1表达在损伤一周内显著升高。Hv1仅在中枢神经系统内的小胶质细胞中表达，提示小胶质细胞参与呼吸爆发时ROS的产生和质子挤压。在损伤后3 d， Hv1的缺失显著减弱了组织酸中毒、NADPH氧化酶2 （NOX2）的表达和ROS的产生。纳米链分析显示，Hv1基因敲除（KO）小鼠的神经炎症和细胞因子信号标记基因表达降低。此外，流式细胞术检测的Hv1缺乏降低了小胶质细胞的增殖、白细胞浸润和吞噬氧化爆发。重要的是，Hv1 KO小鼠表现出明显改善的运动功能和减少的组织病理学。总的来说，这些数据表明Hv1在调节组织酸中毒、nox2介导的ROS产生和脊髓损伤后的功能结局中发挥重要作用。因此，Hv1质子通道代表了一个潜在的靶点，可能导致新的脊髓损伤治疗策略。
Tissue acidosis is an important secondary injury process in the pathophysiology of traumatic spinal cord injury (SCI). To date, no studies have examined the role of proton extrusion as mechanism of pathological acidosis in SCI. In the present study, we hypothesized that the phagocyte-specific proton channel Hv1 mediates hydrogen proton extrusion after SCI, contributing to increased extracellular acidosis and poor long-term outcomes. Using a contusion model of SCI in adult female mice, we demonstrated that tissue pH levels are markedly lower during the first week after SCI. Acidosis was most evident at the injury site, but also extended into proximal regions of the cervical and lumbar cord. Tissue reactive oxygen species (ROS) levels and expression of Hv1 were significantly increased during the week of injury. Hv1 was exclusively expressed in microglia within the CNS, suggesting that microglia contribute to ROS production and proton extrusion during respiratory burst. Depletion of Hv1 significantly attenuated tissue acidosis, NADPH oxidase 2 (NOX2) expression, and ROS production at 3 d post-injury. Nanostring analysis revealed decreased gene expression of neuroinflammatory and cytokine signaling markers in Hv1 knockout (KO) mice. Furthermore, Hv1 deficiency reduced microglia proliferation, leukocyte infiltration, and phagocytic oxidative burst detected by flow cytometry. Importantly, Hv1 KO mice exhibited significantly improved locomotor function and reduced histopathology. Overall, these data suggest an important role for Hv1 in regulating tissue acidosis, NOX2-mediated ROS production, and functional outcome following SCI. Thus, the Hv1 proton channel represents a potential target that may lead to novel therapeutic strategies for SCI.
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影响因子：
4.2
作者：
Farooque, M;Hillered, L;Olsson, Y
通讯作者：
Olsson, Y
DOI：
10.1073/pnas.1308421110
发表时间：
2013-06-25
影响因子：
11.1
作者：
Dodge, James C.;Treleaven, Christopher M.;Shihabuddin, Lamya S.
通讯作者：
Shihabuddin, Lamya S.
影响因子：
--
作者：
Koehn, Liam M;Noor, Natassya M;Habgood, Mark D
通讯作者：
Habgood, Mark D
影响因子：
2.9
作者：
DeCoursey TE
通讯作者：
DeCoursey TE
影响因子：
4.1
作者：
ANDERSON, DK;MEANS, ED;WATERS, TR
通讯作者：
WATERS, TR