M2 microglia-derived exosomes protect the mouse brain from ischemia-reperfusion injury via exosomal miR-124

作者：Yaying Song, Zongwei Li, Tingting He, Meijie Qu, Lu Jiang, Wanlu Li, Xiaojing Shi, Jiaji Pan, Linyuan Zhang, Yongting Wang, Zhijun Zhang, Yaohui Tang, Guo‐Yuan Yang · 发表于：Theranostics · 年份：2019 · DOI：10.7150/thno.30879 · 被引用次数：502 · 研究领域：Extracellular vesicles in disease、MicroRNA in disease regulation、Neuroinflammation and Neurodegeneration Mechanisms

Rationale: Microglia play a critical role in modulating cell death and neurobehavioral recovery in response to brain injury either by direct cell-cell interaction or indirect secretion of trophic factors.Exosomes secreted from cells are well documented to deliver bioactive molecules to recipient cells to modulate cell function.Here, we aimed to identify whether M2 microglia exert neuroprotection after ischemic attack through an exosome-mediated cell-cell interaction.Methods: M2 microglia-derived exosomes were intravenously injected into the mouse brain immediately after middle cerebral artery occlusion.Infarct volume, neurological score, and neuronal apoptosis were examined 3 days after ischemic attack.Exosome RNA and target protein expression levels in neurons and brain tissue were determined for the mechanistic study.Results: Our results showed that the M2 microglia-derived exosomes were taken up by neurons in vitro and in vivo.M2 microglia-derived exosome treatment attenuated neuronal apoptosis after oxygen-glucose deprivation (p<0.05).In vivo results showed that M2 microglia-derived exosome treatment significantly reduced infarct volume and attenuated behavioral deficits 3 days after transient brain ischemia (p<0.05),whereas injection of miR-124 knockdown (miR-124k/d) M2 microglia-derived exosomes partly reversed the neuroprotective effect.Our mechanistic study further demonstrated that ubiquitin-specific protease 14 (USP14) was the direct downstream target of miR-124.Inj...