Zinc triggers microglial activation
Zinc triggers microglial activation
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DOI：
10.1523/jneurosci.1236-08.2008
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发表时间：
2008-05-28
影响因子：
5.3
通讯作者：
Swanson, Raymond A.
中科院分区：
文献类型：
--
作者：
Kauppinen, Tiina M.;Higashi, Youichirou;Swanson, Raymond A.
小胶质细胞是中枢神经系统的常驻免疫细胞。当受到感染、组织损伤或其他信号刺激时，小胶质细胞呈现激活的“变形虫”形态，并释放基质金属蛋白酶、活性氧和其他促炎因子。这种先天免疫反应增强了宿主的防御能力，但也可能导致神经元死亡。在小胶质细胞激活的几种条件下，神经元会释放锌，锌螯合剂可以减少脑缺血和神经退行性疾病动物模型中的神经元死亡。在这里，我们证明锌直接触发小胶质细胞激活。转染核因子-kappa B (NF-kappa B) 报告基因的小胶质细胞在响应 30 mu M 锌时表现出 NF-kappa B 活性数倍增加。培养的小鼠小胶质细胞暴露于 15-30 μM 锌后会增加一氧化氮的产生，增加 F4/80 的表达，改变细胞因子的表达，并呈现激活的形态。通过抑制 NADPH 氧化酶、聚（ADP-核糖）聚合酶-1 (PARP-1) 或 NF-κ B 激活来阻断锌诱导的小胶质细胞激活。将锌直接注射到小鼠大脑中会诱导野生型小鼠的小胶质细胞活化，但不会诱导遗传上缺乏 PARP-1 或 NADPH 氧化酶活性的小鼠的小胶质细胞活化。由脑缺血再灌注诱导的内源性锌释放同样诱导了强烈的小胶质细胞反应，并且该反应被锌螯合剂 CaEDTA 抑制。总之，这些结果表明，细胞外锌通过依次激活 NADPH 氧化酶、PARP-1 和 NF-κ B 来触发小胶质细胞活化。这些发现确定了小胶质细胞活化的新触发因素以及锌可能导致神经系统疾病的先前未被认识的机制。
Microglia are resident immune cells of the CNS. When stimulated by infection, tissue injury, or other signals, microglia assume an activated, "ameboid" morphology and release matrix metalloproteinases, reactive oxygen species, and other proinflammatory factors. This innate immune response augments host defenses, but it can also contribute to neuronal death. Zinc is released by neurons under several conditions in which microglial activation occurs, and zinc chelators can reduce neuronal death in animal models of cerebral ischemia and neurodegenerative disorders. Here, we show that zinc directly triggers microglial activation. Microglia transfected with a nuclear factor-kappa B (NF-kappa B) reporter gene showed a severalfold increase in NF-kappa B activity in response to 30 mu M zinc. Cultured mouse microglia exposed to 15-30 mu M zinc increased nitric oxide production, increased F4/ 80 expression, altered cytokine expression, and assumed the activated morphology. Zinc-induced microglial activation was blocked by inhibiting NADPH oxidase, poly(ADP-ribose) polymerase-1 (PARP-1), or NF-kappa B activation. Zinc injected directly into mouse brain induced microglial activation in wild-type mice, but not in mice genetically lacking PARP-1 or NADPH oxidase activity. Endogenous zinc release, induced by cerebral ischemia-reperfusion, likewise induced a robust microglial reaction, and this reaction was suppressed by the zinc chelator CaEDTA. Together, these results suggest that extracellular zinc triggers microglial activation through the sequential activation of NADPH oxidase, PARP-1, and NF-kappa B. These findings identify a novel trigger for microglial activation and a previously unrecognized mechanism by which zinc may contribute to neurological disorders.