The P2Y12 receptor regulates microglial activation by extracellular nucleotides
The P2Y12 receptor regulates microglial activation by extracellular nucleotides
复制标题
DOI：
10.1038/nn1805
复制
发表时间：
2006-12-01
影响因子：
25
通讯作者：
Julius, David
中科院分区：
文献类型：
--
作者：
Haynes, Sharon E.;Hollopeter, Gunther;Julius, David
小胶质细胞是中枢神经系统的主要免疫哨兵。损伤后，这些细胞迁移或向组织损伤部位延伸过程。CNS损伤伴随着核苷酸的释放，作为小胶质细胞活化或趋化的信号。小胶质细胞表达几种嘌呤受体，包括一种G（i）偶联亚型，该亚型与ATP和ADP介导的体外迁移有关。在这里，我们表明，缺乏G（i）-偶联P2 Y（12）受体的小鼠的小胶质细胞表现出正常的基线运动，但不能在体外或体内向核苷酸迁移，迁移或延伸过程。P2 ry（12）（-/-）小鼠中的小胶质细胞显示出朝向活体小鼠中皮质损伤部位的定向分支延伸显著减少。此外，P2 Y（12）表达在“静息”状态下是稳健的，但在小胶质细胞活化后显著降低。这些结果表明，P2 Y（12）是一个主要的网站，在那里的核苷酸作用，以诱导小胶质细胞趋化反应的早期阶段，局部中枢神经系统损伤。
Microglia are primary immune sentinels of the CNS. Following injury, these cells migrate or extend processes toward sites of tissue damage. CNS injury is accompanied by release of nucleotides, serving as signals for microglial activation or chemotaxis. Microglia express several purinoceptors, including a G(i)-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking G(i)-coupled P2Y(12) receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry(12)(-/-) mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y(12) expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y(12) is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.