Activated microglia can suppress neurite outgrowth and synapse recovery in the acute stage following traumatic brain injury (TBI). However, the underlying mechanism has not been clearly elucidated. Exosomes derived from microglia have been reported to play a critical role in microglia-neuron interaction in healthy and pathological brains. Here, we aimed to investigate the role of microglia-derived exosomes in regulating neurite outgrowth and synapse recovery following TBI. In our study, exosomes derived from microglia were co-cultured with stretch-injured neurons in vitro and intravenously injected into mice that underwent fluid percussion injury (FPI) by tail vein injection in vivo. The results showed that microglia-derived exosomes could be absorbed by neurons in vitro and in vivo. Moreover, exosomes derived from stretch-injured microglia decreased the protein levels of GAP43, PSD-95, GluR1, and Synaptophysin and dendritic complexity in stretch-injured neurons in vitro, and reduced GAP43+ NEUN cell percentage and apical dendritic spine density in the pericontusion region in vivo. Motor coordination was also impaired in mice treated with stretch-injured microglia-derived exosomes after FPI. A microRNA microarray showed that the level of miR-5121 was decreased most greatly in exosomes derived from stretch-injured microglia. Overexpression of miR-5121 in stretch-injured microglia-derived exosomes partly reversed the suppression of neurite outgrowth and synapse recovery of neurons both in vitro and in vivo. Moreover, motor coordination in miR-5121 overexpressed exosomes treated mice was significantly improved after FPI. Following mechanistic study demonstrated that miR-5121 might promote neurite outgrowth and synapse recovery by directly targeting RGMa. In conclusion, our finding revealed a novel exosome-mediated mechanism of microglia-neuron interaction that suppressed neurite outgrowth and synapse recovery of neurons following TBI.

活化的小胶质细胞可以在创伤性脑损伤 (TBI) 后的急性期抑制神经突生长和突触恢复。然而，潜在的机制尚未明确阐明。据报道，源自小胶质细胞的外泌体在健康和病理大脑中的小胶质细胞-神经元相互作用中起关键作用。在这里，我们旨在研究小胶质细胞衍生的外泌体在调节 TBI 后神经突生长和突触恢复中的作用。在我们的研究中，来自小胶质细胞的外泌体在体外与拉伸损伤的神经元共培养，并通过体内尾静脉注射将其静脉注射到经历流体撞击损伤 (FPI) 的小鼠体内。结果表明，小胶质细胞衍生的外泌体可以在体外和体内被神经元吸收。而且，来自拉伸损伤小胶质细胞的外泌体在体外降低了拉伸损伤神经元中 GAP43、PSD-95、GluR1 和突触素的蛋白质水平和树突复杂性，并降低了体内周围挫伤区的 GAP43+ NEUN 细胞百分比和顶端树突棘密度. 在 FPI 后用拉伸损伤的小胶质细胞衍生的外泌体治疗的小鼠中，运动协调性也受损。microRNA 微阵列显示，来自拉伸损伤小胶质细胞的外泌体中 miR-5121 的水平下降幅度最大。miR-5121 在拉伸损伤的小胶质细胞衍生的外泌体中的过表达部分逆转了体外和体内神经突生长和神经元突触恢复的抑制。此外，在 FPI 后，miR-5121 过表达的外泌体处理的小鼠的运动协调性显着改善。以下机制研究表明，miR-5121 可能通过直接靶向 RGMa 促进神经突生长和突触恢复。总之，我们的发现揭示了一种新的外泌体介导的小胶质细胞-神经元相互作用机制，可抑制 TBI 后神经元的神经突生长和突触恢复。