Microglia Processes Block the Spread of Damage in the Brain and Require Functional Chloride Channels
Microglia Processes Block the Spread of Damage in the Brain and Require Functional Chloride Channels
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DOI：
10.1002/glia.20874
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发表时间：
2009-11-15
期刊：
影响因子：
6.2
通讯作者：
Macvicar, Brian A.
中科院分区：
文献类型：
--
作者：
Hines, Dustin J.;Hines, Rochelle M.;Macvicar, Brian A.
小胶质细胞表现出两种形式的运动，丝状伪足探测周围脑组织的持续运动，以及响应附近损伤的较大突起的生长。丝状伪足感知和突起生长的机制和功能尚未得到很好的表征，但可能对大脑中的正常免疫功能至关重要。利用双光子激光扫描显微镜，我们研究了小胶质细胞对损伤的反应过程中的突起生长，并探讨了突起生长和丝状伪足运动之间的关系。此外，我们研究了Cl-或K+通道激活的作用，以及肌动蛋白聚合在这两个不同的过程中，因为机制的理解可以提供一个策略来调节小胶质细胞的功能。我们发现，体积敏感性氯离子通道阻滞剂（NPPB，他莫昔芬，DIDS）阻止了小胶质细胞对损伤的反应。与此相反，丝状伪足的延伸过程中的传感是耐氯离子通道抑制剂，表明这些能动的过程有不同的细胞机制。然而，丝状伪足传感和快速过程生长被阻止抑制肌动蛋白聚合。在对照条件下形成病变后，快速生长的突起接触受损区域，这与病变体积减少37%相关。通过Cl-通道阻断、防止肌动蛋白聚合或通过选择性消融小胶质细胞来抑制突起生长都允许病变体积增加并扩散到周围组织中。因此，响应于局灶性脑损伤的过程生长通过防止病变扩展而有益，并表明小胶质细胞代表了对脑损伤的前线防御。(C)2009威利-利斯公司
Microglia cells exhibit two forms of motility, constant movement of filopodia probing surrounding brain tissue, and outgrowth of larger processes in response to nearby damage. The mechanisms and functions of filopodia sensing and process outgrowth are not well characterized but are likely critical for normal immune function in the brain. Using two photon laser scanning microscopy we investigated microglia process outgrowth in response to damage, and explored the relationship between process outgrowth and filopodia movement. Further, we examined the roles of Cl- or K+ channel activation, as well as actin polymerization in these two distinct processes, because mechanistic understanding could provide a strategy to modulate microglia function. We found that volume sensitive Cl- channel blockers (NPPB, tamoxifen, DIDS) prevented the rapid process outgrowth of microglia observed in response to damage. In contrast, filopodia extension during sensing was resistant to Cl- channel inhibitors, indicating that these motile processes have different cellular mechanisms. However, both filopodia sensing and rapid process outgrowth were blocked by inhibition of actin polymerization. Following lesion formation under control conditions, rapidly outgrowing processes contacted the damaged area and this was associated with a 37% decrease in lesion volume. Inhibition of process outgrowth by Cl- channel block, prevention of actin polymerization, or by selectively ablating microglia all allowed lesion volume to increase and spread into the surrounding tissue. Therefore, process outgrowth in response to focal brain damage is beneficial by preventing lesion expansion and suggests microglia represent a front line defence against damage in the brain. (C) 2009 Wiley-Liss, Inc.