Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death
Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death
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DOI：
10.4049/jimmunol.1003600
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发表时间：
2011-04-15
影响因子：
4.4
通讯作者：
Brown, Guy C.
中科院分区：
文献类型：
--
作者：
Neher, Jonas J.;Neniskyte, Urte;Brown, Guy C.
众所周知，死亡和垂死的神经元通过大脑巨噬细胞（小胶质细胞）的吞噬作用被迅速清除。因此，脑炎症期间的神经元损失一直被认为是由于神经元凋亡或坏死死亡后的吞噬。然而，我们在这篇文章中报道，在炎症条件下，大鼠原代培养的神经元和胶质细胞，吞噬作用积极诱导神经元死亡。具体来说，两种炎症细菌配体，脂壁酸或LPS（分别是胶质TLR2和TLR4的激动剂），刺激小胶质细胞增殖，吞噬活性，并在3天内吞噬约30%的神经元。神经元的吞噬依赖于可溶性介质（尤其是过氧亚硝酸盐）的小胶质细胞释放，从而诱导神经元暴露于吃-me信号磷脂酰丝氨酸（PS）。然而，令人惊讶的是，“吃我”信号是可逆的，因此阻断由PS暴露、PS结合蛋白乳脂球表皮生长因子-8及其小胶质玻璃体连接素受体组成的吞噬途径中的任何步骤，足以在不减少炎症的情况下挽救高达90%的神经元。因此，我们的数据表明了一种新型的炎症性神经退行性变，炎症可以导致其他存活的神经元暴露于“吃我”信号，导致它们通过吞噬而死亡。因此，阻断吞噬作用可以预防某些形式的炎症性神经变性，因此在脑感染、创伤、缺血、神经变性和衰老时可能是有益的。中华免疫学杂志，2011,26(6):973- 983。
It is well-known that dead and dying neurons are quickly removed through phagocytosis by the brain's macrophages, the microglia. Therefore, neuronal loss during brain inflammation has always been assumed to be due to phagocytosis of neurons subsequent to their apoptotic or necrotic death. However, we report in this article that under inflammatory conditions in primary rat cultures of neurons and glia, phagocytosis actively induces neuronal death. Specifically, two inflammatory bacterial ligands, lipoteichoic acid or LPS (agonists of glial TLR2 and TLR4, respectively), stimulated microglial proliferation, phagocytic activity, and engulfment of similar to 30% of neurons within 3 d. Phagocytosis of neurons was dependent on the microglial release of soluble mediators (and peroxynitrite in particular), which induced neuronal exposure of the eat-me signal phosphatidylserine (PS). Surprisingly, however, eat-me signaling was reversible, so that blocking any step in a phagocytic pathway consisting of PS exposure, the PS-binding protein milk fat globule epidermal growth factor-8, and its microglial vitronectin receptor was sufficient to rescue up to 90% of neurons without reducing inflammation. Hence, our data indicate a novel form of inflammatory neurodegeneration, where inflammation can cause eat-me signal exposure by otherwise viable neurons, leading to their death through phagocytosis. Thus, blocking phagocytosis may prevent some forms of inflammatory neurodegeneration, and therefore might be beneficial during brain infection, trauma, ischemia, neurodegeneration, and aging. The Journal of Immunology, 2011, 186: 4973-4983.