HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain
HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain
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DOI：
10.1523/jneurosci.3815-05.2006
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发表时间：
2006-06-14
影响因子：
5.3
通讯作者：
Lee, Ja-Kyeong
中科院分区：
文献类型：
--
作者：
Kim, Jung-Bin;Choi, Joon Sig;Lee, Ja-Kyeong
脑缺血性损伤在缺血核心区伴随兴奋性毒性诱导的急性神经元死亡，在半暗带区伴随迟发性损伤过程。然而，知识的直接调解人，连接这两个过程是有限的。在这里，我们证明了高迁移率族蛋白1（HMGB1），一种非组蛋白DNA结合蛋白，在缺血损伤后立即大量释放到细胞外空间，随后诱导缺血后大脑中的神经炎症。短发夹状RNA介导的HMGB1在缺血后脑中的下调抑制了梗死面积、小胶质细胞活化和促炎标记物诱导，表明HMGB1在炎症过程中起着至关重要的作用。在原代皮质培养物和小胶质细胞培养物中进一步证实了细胞外HMGB1的促炎性类胡萝卜素功能。发现HMGB1在NMDA处理的原代皮质培养基中积累，并且发现从这些培养物收集的上清液触发小胶质细胞活化，这是脑炎症的标志。此外，用重组HMGB1处理也诱导小胶质细胞活化，但通过抗HMGB1抗体处理或通过HMGB1 shRNA表达产生的HMGB1耗尽的上清液不诱导，因此证明HMGB1在小胶质细胞活化中的重要作用。总之，这些结果表明，HMGB1作为一种新的促炎性类胡萝卜素因子，连接兴奋性毒性诱导的急性损伤过程和延迟的炎症过程中缺血后的大脑。
Cerebral ischemic injury proceeds with excitotoxicity-induced acute neuronal death in the ischemic core and with delayed damage processes in the penumbra. However, knowledge concerning the direct mediators that connect these two processes is limited. Here, we demonstrate that high-mobility group box 1 (HMGB1), a nonhistone DNA-binding protein, is massively released into the extracellular space immediately after ischemic insult and that it subsequently induces neuroinflammation in the postischemic brain. Short hairpin (sh) RNA-mediated HMGB1 downregulation in the postischemic brain suppressed infarct size, microglia activation, and proinflammatory marker induction, indicating that HMGB1 plays a crucial role in the inflammatory process. The proinflammatory cytokine-like function of extracellular HMGB1 was further verified in primary cortical cultures and microglial cultures. HMGB1 was found to accumulate in NMDA-treated primary cortical culture media, and supernatants collected from these cultures were found to trigger microglia activation, the hallmark of brain inflammation. Moreover, treatment with recombinant HMGB1 also induced microglial activation, but HMGB1-depleted supernatant produced by anti-HMGB1 antibody treatment or by HMGB1 shRNA expression did not, thus demonstrating the essential role of HMGB1 in microglial activation. Together, these results indicate that HMGB1 functions as a novel proinflammatory cytokine-like factor that connects excitotoxicity-induced acute damage processes and delayed inflammatory processes in the postischemic brain.