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The voltage-gated proton channel Hv1 plays a detrimental role in contusion spinal cord injury via extracellular acidosis-mediated neuroinflammation
Brain, Behavior, and Immunity ( IF 15.1 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.bbi.2020.10.005
Yun Li 1 , Rodney M Ritzel 1 , Junyun He 1 , Tuoxin Cao 1 , Boris Sabirzhanov 1 , Hui Li 1 , Simon Liu 1 , Long-Jun Wu 2 , Junfang Wu 3
Affiliation  

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.

中文翻译:

电压门控质子通道 Hv1 通过细胞外酸中毒介导的神经炎症在挫伤性脊髓损伤中起有害作用

组织酸中毒是创伤性脊髓损伤 (SCI) 病理生理学中重要的继发性损伤过程。迄今为止,还没有研究检查质子挤出作为 SCI 病理性酸中毒机制的作用。在本研究中,我们假设吞噬细胞特异性质子通道 Hv1 介导 SCI 后氢质子挤出,导致细胞外酸中毒增加和长期结果不佳。在成年雌性小鼠中使用 SCI 的挫伤模型,我们证明在 SCI 后的第一周内组织 pH 水平显着降低。酸中毒在损伤部位最为明显,但也延伸到颈椎和腰椎的近端区域。在受伤周内,组织活性氧 (ROS) 水平和 Hv1 的表达显着增加。Hv1 仅在 CNS 内的小胶质细胞中表达,表明小胶质细胞在呼吸爆发期间有助于 ROS 产生和质子排出。Hv1 的消耗显着减轻了组织酸中毒、NADPH 氧化酶 2 (NOX2) 表达和损伤后 3 天的 ROS 产生。Nanostring 分析显示 Hv1 基因敲除 (KO) 小鼠中神经炎症和细胞因子信号标志物的基因表达降低。此外,Hv1 缺陷减少了流式细胞术检测到的小胶质细胞增殖、白细胞浸润和吞噬氧化爆发。重要的是,Hv1 KO 小鼠表现出显着改善的运动功能和减少的组织病理学。总体而言,这些数据表明 Hv1 在调节组织酸中毒、NOX2 介导的 ROS 产生和 SCI 后的功能结果中具有重要作用。因此,
更新日期:2021-01-01
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