Migration of perilesional microglia after focal brain injury and modulation by CC chemokine receptor 5:: An in situ time-lapse confocal imaging study
Migration of perilesional microglia after focal brain injury and modulation by CC chemokine receptor 5:: An in situ time-lapse confocal imaging study
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DOI：
10.1523/jneurosci.5171-04.2005
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发表时间：
2005-07-27
影响因子：
5.3
通讯作者：
Mandell, JW
中科院分区：
文献类型：
--
作者：
Carbonell, WS;Murase, SI;Mandell, JW
小胶质细胞对各种刺激迅速产生反应，被认为是急性损伤和慢性神经系统疾病病理生理学的重要参与者。然而，成熟的小胶质细胞对局灶性病变的反应尚未在成年脊椎动物组织中动态表征。在这里，我们使用延时共聚焦显微镜对成年脑损伤小鼠急性分离活体切片进行了病灶周围小胶质细胞的远距离迁移。病灶周围小胶质细胞在损伤后24 h出现广泛迁移，并在3 d达到峰值。瞬时平均迁移速度约为5 μ m/ min，峰值速度约为10 μ m/ min。集体，定向迁移到病变边缘没有观察到可能预期在化学吸引梯度的存在。相反，迁移是自主的，可以建模为随机行走。半胱氨酸-半胱氨酸趋化因子受体5的药物阻断降低了迁移速度和肿瘤周围迁移小胶质细胞的数量，但不影响定向持久性，这表明趋化因子在调节离散迁移参数中的新作用。最后，失神经海马东侧层激活的小胶质细胞没有广泛迁移，而人类免疫缺陷病毒- 1激活的小胶质细胞迁移速度几乎是刺伤损伤处的两倍，表明小胶质细胞对不同刺激的反应不均匀。了解神经损伤后小胶质细胞迁移的特征和具体的分子机制，可以为调节人类疾病中的神经炎症的治疗策略提供新的靶点。
Microglia rapidly become reactive in response to diverse stimuli and are thought to be prominent participants in the pathophysiology of both acute injury and chronic neurological diseases. However, mature microglial reactions to a focal lesion have not been characterized dynamically in adult vertebrate tissue. Here, we present a detailed analysis of long- distance perilesional microglial migration using time- lapse confocal microscopy in acutely isolated living slices from adult brain- injured mice. Extensive migration of perilesional microglia was apparent by 24 h after injury and peaked at 3 d. Average instantaneous migration speeds of similar to 5 mu m/ min and peak speeds > 10 mu m/ min were observed. Collective, directed migration toward the lesion edge was not observed as might be expected in the presence of chemoattractive gradients. Rather, migration was autonomous and could be modeled as a random walk. Pharmacological blockade of the cysteine - cysteine chemokine receptor 5 reduced migration velocity and the number of perilesional migratory microglia without affecting directional persistence, suggesting a novel role for chemokines in modulation of discrete migratory parameters. Finally, activated microglia in the denervated hippocampal stratum oriens did not migrate extensively, whereas human immunodeficiency virus- 1 tat- activated microglia migrated nearly twice as fast as those at the stab lesion, indicating a nonuniform microglial response to different stimuli. Understanding the characteristics and specific molecular mechanisms underlying microglial migration after neural injury could reveal novel targets for therapeutic strategies for modulating neuroinflammation in human diseases.