Xu Fen-Fen, Liu Zhan, Fang Xiao-Xia, Cao Bei-Bei, Huang Yan, Peng Yu-Ping, Qiu Yi-Hua
Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001 China.
Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001 China.
Int Immunopharmacol. 2025 Feb 20;148:114089. doi: 10.1016/j.intimp.2025.114089. Epub 2025 Jan 19.
Parkinson' s disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra (SN). Our research has demonstrated that the levels of interleukin (IL)-17A are elevated in the SN of rodent models of PD, and that IL-17A accelerates neurodegeneration in PD depending on microglial activation. Furthermore, existing studies indicate that exosomes released by activated microglia may play a significant role as mediators of neurodegeneration in PD. Herein, we demonstrated that BV-2-derived exosomes were taken up by ventral mesencephalic (VM) dopaminergic neurons, and mediated IL-17A effect of promoting dopaminergic neuronal injury. IL-17A-treated BV-2-derived exosomes altered neuronal miR-7 and SNCA expression and promoted dopaminergic neuronal injury in vitro. Inhibiting BV-2 exosome formation and secretion by GW4869 alleviated dopaminergic neuronal injury. Silencing ciRS-7 in BV-2 altered neuronal miR-7 and SNCA expression and mitigated dopaminergic neuronal injury. Overexpression of ciRS-7 in VM neurons altered neuronal miR-7 and SNCA expression and promoted dopaminergic neuronal injury. Injection with exosomes derived from IL-17A-treated BV-2 altered ciRS-7, miR-7 and SNCA expression in SN in MPTP-intoxicated mice and promoted nigrostriatal dopaminergic neurodegeneration and motor impairment. However, injection with exosomes derived from IL-17A and ciRS-7-shRNA treated BV-2 attenuates the manifestations mentioned above. These findings suggest that microglia-derived exosomal ciRS-7 mediates IL-17A effect of promoting neurodegeneration via miR-7 and SNCA targets and may provide a new paradigm to study the pathology of PD.
帕金森病（PD）是一种慢性神经退行性疾病，其特征是黑质（SN）中多巴胺能神经元逐渐丧失。我们的研究表明，在PD啮齿动物模型的SN中，白细胞介素（IL）-17A水平升高，并且IL-17A依赖小胶质细胞激活加速PD中的神经退行性变。此外，现有研究表明，活化的小胶质细胞释放的外泌体可能作为PD神经退行性变的介质发挥重要作用。在此，我们证明BV-2来源的外泌体被腹侧中脑（VM）多巴胺能神经元摄取，并介导IL-17A促进多巴胺能神经元损伤的作用。IL-17A处理的BV-2来源的外泌体在体外改变神经元miR-7和α-突触核蛋白（SNCA）表达并促进多巴胺能神经元损伤。用GW4869抑制BV-2外泌体形成和分泌可减轻多巴胺能神经元损伤。在BV-2中沉默环状RNA-7（ciRS-7）可改变神经元miR-7和SNCA表达并减轻多巴胺能神经元损伤。在VM神经元中过表达ciRS-7可改变神经元miR-7和SNCA表达并促进多巴胺能神经元损伤。注射IL-17A处理的BV-2来源的外泌体可改变MPTP中毒小鼠SN中的ciRS-7、miR-7和SNCA表达，并促进黑质纹状体多巴胺能神经退行性变和运动障碍。然而，注射IL-17A和ciRS-7短发夹RNA（shRNA）处理的BV-2来源的外泌体可减轻上述表现。这些发现表明，小胶质细胞来源的外泌体ciRS-7通过miR-7和SNCA靶点介导IL-17A促进神经退行性变的作用，并可能为研究PD的病理学提供新的范例。
