Abstract
Introduction: Microglia are the main type of resident immune cells in the brain. Under different stimuli, microglia exhibit two entirely different functional activated states, termed the pro-inflammatory (M1) phenotype and the anti-inflammatory (M2) phenotype. Almost all cell types can release exosomes, which are considered as important mediators in cell-to-cell communication. Cell-derived exosomal cargo contains a variety of proteins and nucleic acids, which can work locally or stably transferred to recipient cells. Here, we explored the effects of different phenotypes of microglia-derived exosomes on ischemia-induced brain injury. Methods: Primary microglial cells (PMGs) were treated with LPS or IL-4 to induce the M1 or M2 phenotype, respectively. Exosomes were isolated from the cell culture supernatant. Neuronal apoptosis was examined after oxygen-glucose deprivation (OGD) treatment with different exosomes. Transient middle cerebral artery occlusion (MCAO) was used as the in vivo ischemic stroke model to observe the effects of different phenotypes of microglia-derived exosomes on brain injury. Protein profiles were investigated to screen the candidate molecules that mediate distinct functions. Results: Exosomes derived from different phenotypes of microglia have similar diameter, density and exosomal markers. PMGs-derived exosomes can be taken up by neurons. M1 microglia-derived exosomes increased neuronal apoptosis after OGD treatment than OGD alone, while M2 microglia-derived exosomes attenuated neuronal apoptosis. In vivo results revealed that M2 microglia-derived exosomes alleviated brain infarct size and neurological deficits. Besides, M1 microglia-derived exosomes aggravated brain damage. Proteomic analysis showed that the expression of complement-related proteins in M1 microglia-derived exosomes was significantly upregulated than that of M2 microglia-derived exosomes, while the underlying mechanism mediated by specific proteins needs further verification. Conclusions: We demonstrated that M1 microglia-derived exosomes could aggravate ischemic brain injury, while M2 microglia-derived exosomes attenuated this phenomenon. We will explore the detailed mechanisms in the future.
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