Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure

作者：Marta Lombardi, Roberta Parolisi, Federica Scaroni, Elisabetta Bonfanti, Alice Gualerzi, Martina Gabrielli, Nicole Kerlero de Rosbo, Antonio Uccelli, Paola Giussani, Paola Viani, Cecília Garlanda, Maria P. Abbracchio, Linda Chaabane, Annalisa Buffo, Marta Fumagalli, Claudia Verderio · 发表于：Acta Neuropathologica · 年份：2019 · DOI：10.1007/s00401-019-02049-1 · 被引用次数：185 · 研究领域：Extracellular vesicles in disease、Neuroinflammation and Neurodegeneration Mechanisms、Immune cells in cancer

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 differ...