Norepinephrine Modulates the Motility of Resting and Activated Microglia via Different Adrenergic Receptors
Norepinephrine Modulates the Motility of Resting and Activated Microglia via Different Adrenergic Receptors
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DOI：
10.1074/jbc.m113.458901
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发表时间：
2013-05-24
影响因子：
4.8
通讯作者：
Traynelis, Stephen F.
中科院分区：
文献类型：
--
作者：
Gyoneva, Stefka;Traynelis, Stephen F.
小胶质细胞是中枢神经系统（CNS）的常驻免疫细胞，通过不断移动其精细过程来监测大脑组织稳态的紊乱。小胶质细胞对组织损伤的反应是通过激活ATP/ADP受体，然后定向过程延伸到受损区域。几种神经退行性疾病的一个共同特征是去甲肾上腺素的丧失，这可能导致相关的神经炎症。我们对去甲肾上腺素（NE）对小胶质细胞特异性绿色荧光蛋白表达增强的小鼠急性脑切片中小胶质细胞过程动力学的影响进行了高分辨率分析。在切片上使用NE可导致小胶质细胞明显的突起回缩。定量PCR分析肾上腺素能受体的表达表明，静息小胶质细胞主要表达β(2)受体，但在LPS诱导的促炎条件下转换表达α (2A)受体。尽管受体表达不同，NE在体外凝胶基质基质培养的静息和lps激活的小胶质细胞中都引起了过程收缩。亚型选择性受体激动剂和拮抗剂的使用证实了β(2)受体参与介导静息细胞中的小胶质过程动力学，α (2A)受体参与活化细胞中的小胶质过程动力学。NE与ATP共同作用于静息小胶质细胞阻断了离体小胶质细胞中ATP诱导的过程延伸和迁移，β(2)受体拮抗剂延长了ATP在脑片组织中的作用，提示小胶质细胞中肾上腺素能和嘌呤能信号传导之间存在交叉对话。这些数据表明，神经递质NE可以调节小胶质细胞的运动，从而在NE水平升高或降低的致病性情况下影响小胶质细胞的功能。
Microglia, the resident immune cells of the central nervous system (CNS), monitor the brain for disturbances of tissue homeostasis by constantly moving their fine processes. Microglia respond to tissue damage through activation of ATP/ADP receptors followed by directional process extension to the damaged area. A common feature of several neurodegenerative diseases is the loss of norepinephrine, which might contribute to the associated neuroinflammation. We carried out a high resolution analysis of the effects of norepinephrine (NE) on microglial process dynamics in acute brain slices from mice that exhibit microglia-specific enhanced green fluorescent protein expression. Bath application of NE to the slices resulted in significant process retraction in microglia. Analysis of adrenergic receptor expression with quantitative PCR indicated that resting microglia primarily express beta(2) receptors but switch expression to alpha(2A) receptors under proinflammatory conditions modeled by LPS treatment. Despite the differential receptor expression, NE caused process retraction in both resting and LPS-activated microglia cultured in the gelatinous substrate Matrigel in vitro. The use of subtype-selective receptor agonists and antagonists confirmed the involvement of beta(2) receptors in mediating microglial process dynamics in resting cells and alpha(2A) receptors in activated cells. Co-application of NE with ATP to resting microglia blocked the ATP-induced process extension and migration in isolated microglia, and beta(2) receptor antagonists prolonged ATP effects in brain slice tissues, suggesting the presence of cross-talk between adrenergic and purinergic signaling in microglia. These data show that the neurotransmitter NE can modulate microglial motility, which could affect microglial functions in pathogenic situations of either elevated or reduced NE levels.