UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis
UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis
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DOI：
10.1038/nature05704
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发表时间：
2007-04-26
期刊：
影响因子：
64.8
通讯作者：
Inoue, Kazuhide
中科院分区：
文献类型：
--
作者：
Koizumi, Schuichi;Shigemoto-Mogami, Yukari;Inoue, Kazuhide
小胶质细胞，大脑免疫细胞，参与死亡细胞或危险碎片的清除，这对维持大脑功能至关重要。当邻近的细胞受伤时，小胶质细胞迅速向其移动或延伸过程以吞噬受伤的细胞。由于细胞在受到刺激（1，2）或损伤（3，4）时会释放或泄漏ATP，因此细胞外核苷酸被认为参与了这些事件。事实上，ATP在体外（5，6）和体内（3，4）触发了小胶质细胞运动性的动态变化，这是一种以前未被认识到的小胶质细胞趋化性机制（5，6）;相反，小胶质细胞吞噬作用只受到有限的关注。在这里，我们表明，小胶质细胞表达代谢型P2 Y（6）受体，其激活内源性激动剂UDP触发小胶质细胞吞噬作用。UDP以P2 Y（6）受体依赖的方式促进微球的摄取，这在体内和体外海马神经元被海人酸损伤时通过内源性UDP的泄漏来模拟。此外，在大鼠中全身给予红藻氨酸导致海马CA 1和CA 3区域的神经元细胞死亡，观察到与活化的小胶质细胞共定位的编码P2 Y（6）受体的信使RNA增加。因此，当神经元受损时，P2 Y（6）受体上调，并且可以通过感测可扩散的UDP信号而充当吞噬作用的传感器，这是P2受体在小胶质细胞中的先前未知的病理生理学功能。
Microglia, brain immune cells, engage in the clearance of dead cells or dangerous debris, which is crucial to the maintenance of brain functions. When a neighbouring cell is injured, microglia move rapidly towards it or extend a process to engulf the injured cell. Because cells release or leak ATP when they are stimulated(1,2) or injured(3,4), extracellular nucleotides are thought to be involved in these events. In fact, ATP triggers a dynamic change in the motility of microglia in vitro(5,6) and in vivo(3,4), a previously unrecognized mechanism underlying microglial chemotaxis(5,6); in contrast, microglial phagocytosis has received only limited attention. Here we show that microglia express the metabotropic P2Y(6) receptor whose activation by endogenous agonist UDP triggers microglial phagocytosis. UDP facilitated the uptake of microspheres in a P2Y(6)-receptor-dependent manner, which was mimicked by the leakage of endogenous UDP when hippocampal neurons were damaged by kainic acid in vivo and in vitro. In addition, systemic administration of kainic acid in rats resulted in neuronal cell death in the hippocampal CA1 and CA3 regions, where increases in messenger RNA encoding P2Y(6) receptors that colocalized with activated microglia were observed. Thus, the P2Y(6) receptor is upregulated when neurons are damaged, and could function as a sensor for phagocytosis by sensing diffusible UDP signals, which is a previously unknown pathophysiological function of P2 receptors in microglia.