Wirenfeldt Martin, Dissing-Olesen Lasse, Anne Babcock Alicia, Nielsen Marianne, Meldgaard Michael, Zimmer Jens, Azcoitia Iñigo, Leslie Robert Graham Quinton, Dagnaes-Hansen Frederik, Finsen Bente
Medical Biotechnology Center, Institute of Medical Biology, University of Southern Denmark, Odense, Denmark.
Am J Pathol. 2007 Aug;171(2):617-31. doi: 10.2353/ajpath.2007.061044. Epub 2007 Jun 28.
Microglial population expansion occurs in response to neural damage via processes that involve mitosis and immigration of bone marrow-derived cells. However, little is known of the mechanisms that regulate clearance of reactive microglia, when microgliosis diminishes days to weeks later. We have investigated the mechanisms of microglial population control in a well-defined model of reactive microgliosis in the mouse dentate gyrus after perforant pathway axonal lesion. Unbiased stereological methods and flow cytometry demonstrate significant lesion-induced increases in microglial numbers. Reactive microglia often occurred in clusters, some having recently incorporated bromodeoxyuridine, showing that proliferation had occurred. Annexin V labeling and staining for activated caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling showed that apoptotic mechanisms participate in dissolution of the microglial response. Using bone marrow chimeric mice, we found that the lesion-induced proliferative capacity of resident microglia superseded that of immigrant microglia, whereas lesion-induced kinetics of apoptosis were comparable. Microglial numbers and responses were severely reduced in bone marrow chimeric mice. These results broaden our understanding of the microglial response to neural damage by demonstrating that simultaneously occurring mitosis and apoptosis regulate expansion and reduction of both resident and immigrant microglial cell populations.
小胶质细胞数量的增加是对神经损伤的反应，其过程涉及有丝分裂和骨髓来源细胞的迁移。然而，对于在小胶质细胞增生在数天至数周后消退时，调节反应性小胶质细胞清除的机制却知之甚少。我们在小鼠齿状回穿通通路轴突损伤后反应性小胶质细胞增生的明确模型中，研究了小胶质细胞数量控制的机制。无偏倚的立体学方法和流式细胞术表明，损伤显著诱导小胶质细胞数量增加。反应性小胶质细胞常成簇出现，有些最近掺入了溴脱氧尿苷，表明发生了增殖。膜联蛋白V标记以及活化的半胱天冬酶-3和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记染色表明，凋亡机制参与了小胶质细胞反应的消退。使用骨髓嵌合小鼠，我们发现损伤诱导的驻留小胶质细胞的增殖能力超过了迁移小胶质细胞，而损伤诱导的凋亡动力学则相当。骨髓嵌合小鼠中的小胶质细胞数量和反应严重减少。这些结果通过证明同时发生的有丝分裂和凋亡调节驻留和迁移小胶质细胞群体的扩增和减少，拓宽了我们对小胶质细胞对神经损伤反应的理解。
