Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells
Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells
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DOI：
10.1002/glia.23475
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发表时间：
2018-10
期刊：
影响因子：
6.2
通讯作者：
Akiko Takeda;Youichi Shinozaki;K. Kashiwagi;N. Ohno;Kei Eto;H. Wake;J. Nabekura;S. Koizumi
中科院分区：
文献类型：
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作者：
Akiko Takeda;Youichi Shinozaki;K. Kashiwagi;N. Ohno;Kei Eto;H. Wake;J. Nabekura;S. Koizumi
兴奋性毒性在脑中的神经元死亡中是众所周知的，并且还与视网膜中的神经元损伤有关。近年来越来越多的证据表明，小胶质细胞在脑兴奋性毒性中起重要作用，但其在视网膜中的作用却很少受到关注。在这里，我们报告说，视网膜兴奋毒性是由小胶质细胞介导的。为此，我们采用了三种不同的方法，即米诺环素对小胶质细胞的药理学抑制，集落刺激因子1受体（PLX 5622）拮抗剂的药理学消融，以及使用Iba 1-tTA：：DTAtetO/tetO小鼠对小胶质细胞的遗传消融。玻璃体内注射NMDA可增加视网膜神经节细胞（RGCs）的凋亡数量，随后减少RGCs的数量。虽然小胶质细胞没有直接响应NMDA，他们成为反应早于RGC的损害。抑制或消融小胶质细胞保护RGCs免受NMDA的侵害。我们发现了促炎细胞因子基因的上调，包括Il 1b，Il 6和Tnfa，其中Tnfa被米诺环素选择性阻断。PLX 5622还抑制Tnfa表达。肿瘤坏死因子α（TNFα）信号在小胶质细胞中的分布较早，随后扩散到其他细胞类型。米诺环素和PLX 5622显著减弱了小胶质细胞和其他细胞中的TNFα上调，表明小胶质细胞在TNFα诱导中发挥了重要作用。通过siRNA抑制TNFα和敲低TNF受体1均保护RGCs免受NMDA的侵害。总之，我们的数据表明，小胶质细胞表型改变为神经毒性细胞是NMDA诱导的RGC变性的关键事件，表明非细胞自主机制在视网膜神经元兴奋性毒性中的重要性。
Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1‐tTA::DTAtetO/tetO mice. Intravitreal injection of NMDA increased the number of apoptotic retinal ganglion cells (RGCs) followed by reduction in the number of RGCs. Although microglia did not respond to NMDA directly, they became reactive earlier than RGC damages. Inhibition or ablation of microglia protected RGCs against NMDA. We found up‐regulation of proinflammatory cytokine genes including Il1b, Il6 and Tnfa, among which Tnfa was selectively blocked by minocycline. PLX5622 also suppressed Tnfa expression. Tumor necrosis factor α (TNFα) signals were restricted in microglia at very early followed by spreading into other cell types. TNFα up‐regulation in microglia and other cells were significantly attenuated by minocycline and PLX5622, suggesting a central role of microglia for TNFα induction. Both inhibition of TNFα and knockdown of TNF receptor type 1 by siRNA protected RGCs against NMDA. Taken together, our data demonstrate that a phenotypic change of microglia into a neurotoxic one is a critical event for the NMDA‐induced degeneration of RGCs, suggesting an importance of non‐cell‐autonomous mechanism in the retinal neuronal excitotoxicity.