The p38α MAPK regulates microglial responsiveness to diffuse traumatic brain injury.
The p38α MAPK regulates microglial responsiveness to diffuse traumatic brain injury.
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DOI：
10.1523/jneurosci.5399-12.2013
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发表时间：
2013-04-03
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影响因子：
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通讯作者：
Van Eldik LJ
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文献类型：
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作者：
Bachstetter AD;Rowe RK;Kaneko M;Goulding D;Lifshitz J;Van Eldik LJ
创伤性脑损伤（TBI）后的神经病理学是直接冲击损伤和继发性损伤机制共同作用的结果。未解决的创伤后神经胶质活化是一种继发性损伤机制，其导致TBI动物模型和人类头部损伤患者的神经炎症慢性状态。我们最近使用体外模型证明，小胶质细胞中的p38α MAPK信号传导是促进细胞因子产生的关键事件，以响应不同的疾病相关应激源和随后的炎症性神经元功能障碍。根据这些发现，我们假设小胶质细胞中的p38α信号通路可能是弥漫性TBI后继发性神经病理学后遗症的原因。小胶质细胞p38α缺陷（p38α KO）的小鼠可免受TBI诱导的运动缺陷和突触蛋白丢失。在野生型（WT）小鼠中，弥漫性TBI产生持续至少7天的小胶质细胞形态学激活;然而，p38α KO小鼠未能激活该反应。出乎意料的是，我们发现与损伤的WT小鼠相比，损伤的p38α KO小鼠中早期急性期细胞因子和趋化因子水平的峰值增加。p38α KO小鼠中细胞因子水平升高不能通过巨噬细胞或中性粒细胞浸润增加或星形胶质细胞增生增加来解释。损伤后7天，细胞因子和趋化因子水平在损伤的WT小鼠中保持升高，但在p38α KO小鼠中没有。总之，这些数据表明，p38α通过急性减弱早期促炎细胞因子激增来平衡炎症反应，同时使TBI后的慢性小胶质细胞活化永久化。
Neuropathology following traumatic brain injury (TBI) is the result of both the immediate impact injury and secondary injury mechanisms. Unresolved post-traumatic glial activation is a secondary injury mechanism that contributes to a chronic state of neuroinflammation in both animal models of TBI and human head injury patients. We recently demonstrated, using in vitro models, that p38α MAPK signaling in microglia is a key event in promoting cytokine production in response to diverse disease-relevant stressors and subsequent inflammatory neuronal dysfunction. From these findings, we hypothesized that the p38α signaling pathway in microglia could be contributing to the secondary neuropathologic sequelae following a diffuse TBI. Mice where microglia were p38α deficient (p38α KO) were protected against TBI induced motor deficits and synaptic protein loss. In wild type (WT) mice, diffuse TBI produced microglia morphological activation that lasted for at least 7 days; however, p38α KO mice failed to activate this response. Unexpectedly, we found that the peak of the early, acute phase cytokine and chemokine levels was increased in injured p38α KO mice compared to injured WT mice. The increased cytokine levels in the p38α KO mice could not be accounted for by more infiltration of macrophages or neutrophils, or increased astrogliosis. By 7 days after injury, the cytokine and chemokine levels remained elevated in injured WT mice but not in p38α KO mice. Together, these data suggest that p38α balances the inflammatory response by acutely attenuating the early proinflammatory cytokine surge, while perpetuating the chronic microglia activation after TBI.