Microglial phagocytosis attenuated by short-term exposure to exogenous ATP through P2X7 receptor action
Microglial phagocytosis attenuated by short-term exposure to exogenous ATP through P2X7 receptor action
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DOI：
10.1111/j.1471-4159.2009.06409.x
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发表时间：
2009-12-01
影响因子：
4.7
通讯作者：
Tzeng, Shun-Fen
中科院分区：
文献类型：
--
作者：
Fang, Kuan-Min;Yang, Chung-Shi;Tzeng, Shun-Fen
小胶质细胞是中枢神经系统内的巨噬细胞，负责清除退化的细胞碎片，对中枢神经系统损伤后的组织重建和修复至关重要。ATP可以在CNS损伤后大量释放，并且可以通过亲离子型P2 X和亲代谢型P2 Y受体介导小胶质细胞活性。本研究表明，暴露于高浓度的ATP 30分钟迅速诱导小胶质细胞的细胞骨架的变化，并显着减弱小胶质细胞的吞噬作用。药理学方法表明，ATP诱导的小胶质细胞吞噬活性的抑制是由于P2 X（7）R激活，而不是P2 YR。P2 X（7）R的激动剂2 '-3'-O-（4-苯甲酰基）苯甲酰基-ATP（BzATP）激活P2 X（7）R后，小胶质细胞吞噬活性出现了非钙依赖性降低。此外，通过慢病毒介导的shRNA干扰敲低P2 X（7）R表达或通过特异性拮抗剂氧化ATP（oxATP）和亮蓝G阻断P2 X（7）R活化，有效地恢复了ATP和BzATP处理的小胶质细胞的吞噬活性。我们的研究结果表明，P2 X（7）R激活可能会诱导形成一个钙离子非依赖性信号复合物，这导致小胶质细胞吞噬功能的减少。这表明，短期暴露于ATP可能会导致中枢神经系统损伤后小胶质细胞通过P2 X（7）R激活对组织碎片的清除不足，而阻断该受体可能会保护小胶质细胞的吞噬作用并促进中枢神经系统组织修复。
Microglia, the CNS resident macrophages responsible for the clearance of degenerating cellular fragments, are essential to tissue remodeling and repair after CNS injury. ATP can be released in large amounts after CNS injury and may mediate microglial activity through the ionotropic P2X and the metabotropic P2Y receptors. This study indicates that exposure to a high concentration of ATP for 30 min rapidly induces changes of the microglial cytoskeleton, and significantly attenuates microglial phagocytosis. A pharmacological approach showed that ATP-induced inhibition of microglial phagocytotic activity was due to P2X(7)R activation, rather than that of P2YR. Activation of P2X(7)R by its agonist, 2'-3'-O-(4-benzoyl)benzoyl-ATP (BzATP), produced a Ca2+-independent reduction in microglial phagocytotic activity. In addition, the knockdown of P2X(7)R expression by lentiviral-mediated shRNA interference or the blockade of P2X(7)R activation by the specific antagonists, oxidized ATP (oxATP) and brilliant blue G, has efficiently restored the phagocytotic activity of ATP and BzATP-treated microglia. Our results reveal that P2X(7)R activation may induce the formation of a Ca2+-independent signaling complex, which results in the reduction of microglial phagocytosis. This suggests that exposure to ATP for a short-term period may cause insufficient clearance of tissue debris by microglia through P2X(7)R activation after CNS injury, and that blockade of this receptor may preserve the phagocytosis of microglia and facilitate CNS tissue repair.