High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4.
High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4.
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DOI：
10.1002/glia.22581
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发表时间：
2014-01
期刊：
影响因子：
6.2
通讯作者：
Dhandapani KM
中科院分区：
文献类型：
--
作者：
Laird MD;Shields JS;Sukumari-Ramesh S;Kimbler DE;Fessler RD;Shakir B;Youssef P;Yanasak N;Vender JR;Dhandapani KM
创伤性脑损伤（TBI）是全世界死亡和发病的主要原因。脑水肿是一种危及生命的并发症，会导致 TBI 后颅内压 (ICP) 升高和临床预后不良。不幸的是，减少创伤后水肿的治疗方案仍然不够理想，部分原因是缺乏可行的治疗靶点。在此，我们检验了大脑先天免疫反应导致 TBI 后水肿发展的假设。我们的结果表明，高迁移率组盒蛋白 1 (HMGB1) 通过 NR2B 介导的机制从坏死神经元中释放。 HMGB1 在临床上与患者的 ICP 升高相关，并在功能上促进小鼠 TBI 后的脑水肿。 HMGB1 的有害作用至少部分是通过小胶质细胞 Toll 样受体 4 (TLR4) 的激活以及随后星形胶质细胞水通道水通道蛋白 4 (AQP4) 的表达来介导的。遗传或药理学 (VGX-1027) TLR4 抑制可减弱神经炎症反应并限制创伤后水肿，并延迟临床上可实施的治疗窗。人类和啮齿动物组织培养研究进一步明确了细胞机制，证明神经元 HMGB1 以 TLR4 依赖性机制启动小胶质细胞释放白细胞介素 6 (IL-6)。反过来，小胶质细胞 IL-6 增加了 AQP4 的星形胶质细胞表达。总而言之，这些数据表明小胶质细胞是创伤后脑水肿的关键介质，并表明 HMGB1-TLR4 信号传导促进 TBI 后的神经血管功能障碍。
Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor-4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post-traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI.