Centre for Discovery Brain Sciences, The University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
EMBL Heidelberg, Meyerhofstraße 1, 69117 Heidelberg, Germany.
Development. 2019 May 10;146(9):dev174698. doi: 10.1242/dev.174698.
Moderate or severe traumatic brain injury (TBI) causes widespread neuronal cell death. Microglia, the resident macrophages of the brain, react to injury by migrating to the lesion site, where they phagocytose cellular debris. Microglial phagocytosis can have both beneficial (e.g. debris clearance) and detrimental (e.g. respiratory burst, phagoptosis) consequences. Hence, whether the overall effect of microglial phagocytosis after brain injury is neuroprotective or neurotoxic is not known. Here, we establish a system with which to carry out dynamic real-time analyses of the mechanisms regulating cell death after brain injury We show that mechanical injury to the larval zebrafish brain induces distinct phases of primary and secondary cell death. Excitotoxicity contributes to secondary cell death in zebrafish, reflecting findings from mammals. Microglia arrive at the lesion site within minutes of injury, where they rapidly engulf dead cells. Importantly, the rate of secondary cell death is increased when the rapid removal of cellular debris by microglia is reduced pharmacologically or genetically. In summary, our results provide evidence that microglial debris clearance is neuroprotective after brain injury .
中度或重度创伤性脑损伤 (TBI) 会导致广泛的神经元细胞死亡。小胶质细胞是大脑的常驻巨噬细胞，它们会迁移到损伤部位，吞噬细胞碎片。小胶质细胞的吞噬作用可能既有有益的（例如清除碎片），也有有害的（例如呼吸爆发、吞噬作用）后果。因此，脑损伤后小胶质细胞吞噬作用的总体影响是神经保护还是神经毒性尚不清楚。在这里，我们建立了一个系统，可以对脑损伤后调节细胞死亡的机制进行动态实时分析。我们表明，对幼虫斑马鱼大脑的机械损伤会诱导原发性和继发性细胞死亡的不同阶段。兴奋性毒性导致斑马鱼的继发性细胞死亡，反映了哺乳动物的发现。小胶质细胞在损伤后几分钟内到达损伤部位，并迅速吞噬死亡细胞。重要的是，当通过药理学或遗传学减少小胶质细胞快速清除细胞碎片时，继发性细胞死亡的速度会增加。总之，我们的结果提供了证据，表明脑损伤后小胶质细胞清除细胞碎片具有神经保护作用。
