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首页> 外文期刊>Journal of neuroinflammation >Diverse activation of microglia by chemokine (C-C motif) ligand 2 overexpression in brain
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Diverse activation of microglia by chemokine (C-C motif) ligand 2 overexpression in brain

机译：趋化因子（C-C主题）配体2在脑中的过度表达对小胶质细胞的多种激活。

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Background The chemokine (C-C motif) ligand 2 (CCL2) is a monocyte chemoattractant protein that mediates macrophage recruitment and migration during peripheral and central nervous system (CNS) inflammation. Methods To determine the impact of CCL2 in inflammation in vivo and to elucidate the CCL2-induced polarization of activated brain microglia, we delivered CCL2 into the brains of wild-type mice via recombinant adeno-associated virus serotype 9 (rAAV-9) driven by the chicken β-actin promoter. We measured microglial activation using histological and chemical measurement and recruitment of monocytes using histology and flow cytometry. Results The overexpression of CCL2 in the CNS induced significant activation of brain resident microglia. CD45 and major histocompatibility complex class II immunoreactivity significantly increased at the sites of CCL2 administration. Histological characterization of the microglial phenotype revealed the elevation of “classically activated” microglial markers, such as calgranulin B and IL-1β, as well as markers associated with “alternative activation” of microglia, including YM1 and arginase 1. The protein expression profile in the hippocampus demonstrated markedly increased levels of IL-6, GM-CSF and eotaxin (CCL-11) in response to CCL2, but no changes in the levels of other cytokines, including TNF-α and IFN-γ. Moreover, real-time PCR analysis confirmed increases in mRNA levels of gene transcripts associated with neuroinflammation following CCL2 overexpression. Finally, we investigated the chemotactic properties of CCL2 in vivo by performing adoptive transfer of bone marrow–derived cells (BMDCs) isolated from donor mice that ubiquitously expressed green fluorescent protein. Flow cytometry and histological analyses indicated that BMDCs extravasated into brain parenchyma and colabeled with microglial markers. Conclusion Taken together, our results suggest that CCL2 strongly activates resident microglia in the brain. Both pro- and anti-inflammatory activation of microglia were prominent, with no bias toward the M1 or M2 phenotype in the activated cells. As expected, CCL2 overexpression actively recruited circulating monocytes into the CNS. Thus, CCL2 expression in mouse brain induces microglial activation and represents an efficient method for recruitment of peripheral macrophages.
机译：背景趋化因子（C-C基序）配体2（CCL2）是一种单核细胞趋化蛋白，在外周和中枢神经系统（CNS）炎症过程中介导巨噬细胞募集和迁移。方法为了确定CCL2对体内炎症的影响，并阐明CCL2诱导的活化的脑小胶质细胞的极化，我们通过重组腺相关病毒血清型9（rAAV-9）将CCL2递送至野生型小鼠的大脑，鸡β-肌动蛋白启动子。我们使用组织学和化学方法测量小胶质细胞的激活，并使用组织学和流式细胞术测量单核细胞的募集。结果中枢神经系统中CCL2的过表达诱导脑内小胶质细胞的显着活化。 CD45和主要组织相容性复合物II类免疫反应性在CCL2给药部位显着增加。小胶质细胞表型的组织学表征显示，“经典激活的”小胶质细胞标记物（例如钙粒蛋白B和IL-1β）以及与小胶质细胞的“替代激活”相关的标记物（包括YM1和精氨酸酶1）升高。海马表现出对CCL2的应答，IL-6，GM-CSF和嗜酸性粒细胞趋化因子（CCL-11）的水平明显升高，但其他细胞因子（包括TNF-α和IFN-γ）的水平没有变化。此外，实时PCR分析证实CCL2过表达后与神经炎症相关的基因转录产物mRNA水平增加。最后，我们通过从普遍表达绿色荧光蛋白的供体小鼠中分离出的骨髓衍生细胞（BMDC）进行过继转移，研究了CCL2在体内的趋化特性。流式细胞仪和组织学分析表明，BMDCs渗入脑实质并与小胶质细胞标记物共同标记。结论综上所述，我们的结果表明CCL2可以强烈激活大脑中的小胶质细胞。小胶质细胞的促炎和抗炎激活均很明显，在激活的细胞中对M1或M2表型没有偏见。不出所料，CCL2过表达将循环单核细胞主动募集到CNS中。因此，小鼠大脑中的CCL2表达诱导小胶质细胞活化，并代表了募集外周巨噬细胞的有效方法。

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