Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure
Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure
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DOI：
10.1007/s00401-019-02049-1
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发表时间：
2019-12-01
影响因子：
12.7
通讯作者：
Verderio, Claudia
中科院分区：
文献类型：
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作者：
Lombardi, Marta;Parolisi, Roberta;Verderio, Claudia
小胶质细胞是高度可塑性的免疫细胞，存在于连续的激活状态。通过塑造少突胶质前体细胞（OPCs）的功能，小胶质细胞可以分化成髓鞘形成细胞，参与多发性硬化症期间髓鞘损伤和再髓鞘形成。然而，小胶质细胞在支持或抑制髓磷脂修复中的作用模式仍不清楚。在这里，我们分析了促炎或促再生小胶质细胞在体外产生的细胞外囊泡（EVs）对小鼠胼胝体中溶卵磷脂注射引起的脱髓鞘病变的OPCs的影响。髓磷脂蛋白的免疫标记和电镜显示，促炎小胶质细胞释放的EVs可阻断髓鞘再生，而小胶质细胞与免疫抑制间充质干细胞共培养产生的EVs可促进OPC募集和髓鞘修复。在原代OPC培养物中解剖了负责有害和有益EV行为的分子机制。通过将单独培养或与星形胶质细胞一起培养的OPC暴露于炎性ev中，我们观察到仅在星形胶质细胞存在时OPC成熟受阻，暗示这些细胞参与了髓鞘再生失败。免疫组织化学和qPCR分析显示，生化分离表明，炎性EV货物可能会将星形胶质细胞转化为有害细胞，而EV的表面脂质成分促进OPC迁移和/或分化，将EV脂质与髓鞘修复联系起来。尽管脂质物种促进OPC成熟的机制仍有待完全确定，但我们首次证明了囊泡鞘磷脂1磷酸刺激OPC迁移，这是髓磷脂修复的第一个基本步骤。从这项研究中，小胶质细胞EVs作为多模式和多靶点的信号介质，能够影响髓鞘病变周围的OPCs和星形胶质细胞，这可能被用来开发髓鞘修复的新方法，不仅用于多发性硬化症，还用于以脱髓鞘为特征的神经和神经精神疾病。
Microglia are highly plastic immune cells which exist in a continuum of activation states. By shaping the function of oligodendrocyte precursor cells (OPCs), the brain cells which differentiate to myelin-forming cells, microglia participate in both myelin injury and remyelination during multiple sclerosis. However, the mode(s) of action of microglia in supporting or inhibiting myelin repair is still largely unclear. Here, we analysed the effects of extracellular vesicles (EVs) produced in vitro by either pro-inflammatory or pro-regenerative microglia on OPCs at demyelinated lesions caused by lysolecithin injection in the mouse corpus callosum. Immunolabelling for myelin proteins and electron microscopy showed that EVs released by pro-inflammatory microglia blocked remyelination, whereas EVs produced by microglia co-cultured with immunosuppressive mesenchymal stem cells promoted OPC recruitment and myelin repair. The molecular mechanisms responsible for the harmful and beneficial EV actions were dissected in primary OPC cultures. By exposing OPCs, cultured either alone or with astrocytes, to inflammatory EVs, we observed a blockade of OPC maturation only in the presence of astrocytes, implicating these cells in remyelination failure. Biochemical fractionation revealed that astrocytes may be converted into harmful cells by the inflammatory EV cargo, as indicated by immunohistochemical and qPCR analyses, whereas surface lipid components of EVs promote OPC migration and/or differentiation, linking EV lipids to myelin repair. Although the mechanisms through which the lipid species enhance OPC maturation still remain to be fully defined, we provide the first demonstration that vesicular sphingosine 1 phosphate stimulates OPC migration, the first fundamental step in myelin repair. From this study, microglial EVs emerge as multimodal and multitarget signalling mediators able to influence both OPCs and astrocytes around myelin lesions, which may be exploited to develop novel approaches for myelin repair not only in multiple sclerosis, but also in neurological and neuropsychiatric diseases characterized by demyelination.