Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury.
Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury.
复制标题
小胶质细胞氧化猝发过程中的质子排出加重创伤性脑损伤后的病理性酸中毒。
作者：
Ritzel RM;He J;Li Y;Cao T;Khan N;Shim B;Sabirzhanov B;Aubrecht T;Stoica BA;Faden AI;Wu LJ;Wu J
酸中毒是研究最少的与神经创伤相关的继发性损伤机制之一。急性脑pH降低与创伤性脑损伤（TBI）患者不良的长期预后相关，然而，其时间动态和潜在机制尚不清楚。作为神经炎症的关键驱动因素，我们假设小胶质细胞直接调节创伤性脑损伤后的酸中毒，从而使神经系统预后恶化。通过对成年雄性小鼠的控制皮质冲击模型，我们发现在损伤后数周内，小胶质细胞内的pH值和病变部位周围的细胞外pH值显著降低。小胶质细胞的增殖和活性氧（ROS）的产生也在第一周增加，反映了病变部位周围细胞外ROS水平的增加。集落刺激因子1受体（CSF1R）抑制剂PLX5622对小胶质细胞的消耗可显著减少损伤后脑细胞外酸中毒、ROS产生和炎症。在机制上，我们发现电压门控质子通道Hv1促进小胶质细胞的氧化爆发活性和酸挤压。与野生型对照相比，缺乏Hv1的小胶质细胞产生ROS和挤出质子的能力降低。重要的是，Hv1缺陷小鼠在TBI后表现出病理性酸中毒和炎症减少，导致长期的神经保护和功能恢复。因此，我们的数据表明，小胶质细胞Hv1质子通道是脑损伤微环境中炎症和酸中毒整合的重要环节。脑损伤引起小胶质细胞及周围病变部位的慢性酸中毒，小胶质细胞耗竭可减轻脑酸中毒和ROS水平，质子通道Hv1促进小胶质细胞外H+和ROS的释放，使预后恶化
Acidosis is among the least studied secondary injury mechanisms associated with neurotrauma. Acute decreases in brain pH correlate with poor long‐term outcome in patients with traumatic brain injury (TBI), however, the temporal dynamics and underlying mechanisms are unclear. As key drivers of neuroinflammation, we hypothesized that microglia directly regulate acidosis after TBI, and thereby, worsen neurological outcomes. Using a controlled cortical impact model in adult male mice we demonstrate that intracellular pH in microglia and extracellular pH surrounding the lesion site are significantly reduced for weeks after injury. Microglia proliferation and production of reactive oxygen species (ROS) were also increased during the first week, mirroring the increase in extracellular ROS levels seen around the lesion site. Microglia depletion by a colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622, markedly decreased extracellular acidosis, ROS production, and inflammation in the brain after injury. Mechanistically, we identified that the voltage‐gated proton channel Hv1 promotes oxidative burst activity and acid extrusion in microglia. Compared to wildtype controls, microglia lacking Hv1 showed reduced ability to generate ROS and extrude protons. Importantly, Hv1‐deficient mice exhibited reduced pathological acidosis and inflammation after TBI, leading to long‐term neuroprotection and functional recovery. Our data therefore establish the microglial Hv1 proton channel as an important link that integrates inflammation and acidosis within the injury microenvironment during head injury. Head injury causes chronic acidosis in microglia and the surrounding lesion site Microglia depletion attenuated brain acidosis and ROS levels The proton channel Hv1 promoted extracellular release of H+ and ROS from microglia and worsened outcome
登录
查看更多内容
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：
8.7
作者：
DeCoursey TE
通讯作者：
DeCoursey TE
DOI：
10.1073/pnas.0902761106
发表时间：
2009-05-05
影响因子：
11.1
作者：
Ramsey, I. Scott;Ruchti, Evelyne;Clapham, David E.
通讯作者：
Clapham, David E.
DOI：
10.1073/pnas.1922788117
发表时间：
2020-09-22
影响因子：
11.1
作者：
Lei F;Cui N;Zhou C;Chodosh J;Vavvas DG;Paschalis EI
通讯作者：
Paschalis EI
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.