Neuronal production of lipocalin-2 as a help-me signal for glial activation.
Neuronal production of lipocalin-2 as a help-me signal for glial activation.
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DOI：
10.1161/strokeaha.114.005733
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发表时间：
2014-07
期刊：
影响因子：
8.3
通讯作者：
Lo EH
中科院分区：
文献类型：
--
作者：
Xing C;Wang X;Cheng C;Montaner J;Mandeville E;Leung W;van Leyen K;Lok J;Wang X;Lo EH
我们探索了损伤神经元释放脂质运载蛋白2作为帮助我信号的假设。使用ELISA和免疫染色的组合在大鼠局灶性脑缺血和人中风脑样品中评估体内脂质运载蛋白-2应答。在体外，将小胶质细胞和星形胶质细胞暴露于脂质运载蛋白-2，并对胶质细胞活化的各种标志物和测定进行定量。通过将来自脂质运载蛋白-2激活的小胶质细胞和星形胶质细胞的条件培养基转移到神经元上来检查神经元到胶质细胞脂质运载蛋白-2信号传导的功能相关性，以观察激活的胶质细胞是否可以保护神经元免受氧-葡萄糖剥夺并促进神经可塑性。在人类中风样本和大鼠脑缺血中，脂质运载蛋白-2的神经元表达显著增加。在原代细胞培养中，将小胶质细胞和星形胶质细胞暴露于脂质运载蛋白-2导致胶质细胞活化。在小胶质细胞中，脂质运载蛋白-2将静息分枝形状转化为具有减少的分支、增加的白细胞介素-10释放和增强的吞噬作用的长杆形态。在星形胶质细胞中，脂质运载蛋白-2上调GFAP、BDNF和血小板反应蛋白-1。脂质运载蛋白-2处理的星形胶质细胞的条件培养基上调突触结合蛋白，脂质运载蛋白-2处理的小胶质细胞的条件培养基上调突触素和PSD 95，并保护神经元免受氧-葡萄糖剥夺。这些发现提供了概念验证，即脂质运载蛋白-2由受损的神经元释放，作为“帮助我”的痛苦信号，激活小胶质细胞和星形胶质细胞成为潜在的促恢复表型。
We explored the hypothesis that injured neurons release lipocalin-2 as a help-me signal. In vivo lipocalin-2 responses were assessed in rat focal cerebral ischemia and human stroke brain samples using a combination of ELISA and immunostaining. In vitro, microglia and astrocytes were exposed to lipocalin-2 and various markers and assays of glial activation were quantified. Functional relevance of neuron-to-glia lipocalin-2 signaling was examined by transferring conditioned media from lipocalin-2-activated microglia and astrocytes onto neurons to see whether activated glia could protect neurons against oxygen-glucose deprivation and promote neuroplasticity. In human stroke samples and rat cerebral ischemia, neuronal expression of lipocalin-2 was significantly increased. In primary cell cultures, exposing microglia and astrocytes to lipocalin-2 resulted in glial activation. In microglia, lipocalin-2 converted resting ramified shapes into a long-rod morphology with reduced branching, increased interleukin-10 release, and enhanced phagocytosis. In astrocytes, lipocalin-2 upregulated GFAP, BDNF and thrombospondin-1. Conditioned media from lipocalin-2-treated astrocytes upregulated synaptotagmin, and conditioned media from lipocalin-2-treated microglia upregulated synaptophysin and PSD95 and protected neurons against oxygen-glucose deprivation. These findings provide proof-of-concept that lipocalin-2 is released by injured neurons as a “help-me” distress signal that activates microglia and astrocytes into potentially pro-recovery phenotypes.