Influence of extracellular zinc on M1 microglial activation.
Influence of extracellular zinc on M1 microglial activation.
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DOI：
10.1038/srep43778
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发表时间：
2017-02-27
影响因子：
4.6
通讯作者：
Saito M
中科院分区：
文献类型：
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作者：
Higashi Y;Aratake T;Shimizu S;Shimizu T;Nakamura K;Tsuda M;Yawata T;Ueba T;Saito M
海马神经元因大脑缺血而释放的细胞外锌会引发小胶质细胞的形态变化。在缺血条件下，小胶质细胞表现出两种相反的激活状态（M1和M2激活），这可能受到微环境的进一步调节。我们研究了细胞外锌对小胶质细胞 M1 激活的作用。当通过脂多糖诱导 M1 激活时，用 30–60μM ZnCl2 预处理小胶质细胞会导致白细胞介素 1 β (IL-1β)、白细胞介素 6 (IL-6) 和肿瘤坏死因子 α (TNFα) 分泌呈剂量依赖性增加。相比之下，细胞渗透性锌螯合剂 TPEN、自由基清除剂 Trolox 和 P2X7 受体拮抗剂 A438079 抑制了锌预处理对小胶质细胞的影响。此外，脑缺血再灌注诱导内源性锌释放，导致 IL-1β、IL-6、TNFα 和小胶质细胞 M1 表面标志物 CD16/32 的表达增加，除了物体识别记忆受损外，没有海马神经元细胞损失。然而，这些效应被锌螯合剂 CaEDTA 抑制。这些发现表明，细胞外锌可能通过 P2X7 受体激活，随后响应触发 M1 激活的刺激而产生活性氧，从而启动小胶质细胞增强促炎细胞因子的产生，并且这些炎症过程可能导致物体识别记忆缺陷。
Extracellular zinc, which is released from hippocampal neurons in response to brain ischaemia, triggers morphological changes in microglia. Under ischaemic conditions, microglia exhibit two opposite activation states (M1 and M2 activation), which may be further regulated by the microenvironment. We examined the role of extracellular zinc on M1 activation of microglia. Pre-treatment of microglia with 30–60 μM ZnCl2 resulted in dose-dependent increases in interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNFα) secretion when M1 activation was induced by lipopolysaccharide administration. In contrast, the cell-permeable zinc chelator TPEN, the radical scavenger Trolox, and the P2X7 receptor antagonist A438079 suppressed the effects of zinc pre-treatment on microglia. Furthermore, endogenous zinc release was induced by cerebral ischaemia–reperfusion, resulting in increased expression of IL-1β, IL-6, TNFα, and the microglial M1 surface marker CD16/32, without hippocampal neuronal cell loss, in addition to impairments in object recognition memory. However, these effects were suppressed by the zinc chelator CaEDTA. These findings suggest that extracellular zinc may prime microglia to enhance production of pro-inflammatory cytokines via P2X7 receptor activation followed by reactive oxygen species generation in response to stimuli that trigger M1 activation, and that these inflammatory processes may result in deficits in object recognition memory.