巨噬细胞迁移抑制因子（MIF）在帕金森病中的作用及机制研究

Parkinson’s disease (PD) is characterized by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. Recent studies have shown that microglia activation-mediated neuroinflammation plays an important role in the process of neuronal degeneration in PD. Over activation of microglia can release amount of pro-inflammatory cytokines and mediators, then initiate pro-inflammatory cascades contribute to DA neuronal damage and loss. Macrophage migration inhibitory factor (MIF) is involved in regulating innate and adaptive immune response. As a proinflammatory cytokine, MIF can promote other inflammatory cytokines and override the immunosuppressive effect of glucocorticoids (GCs). As such MIF has been regarded as an attractive anti-inflammatory pharmacological target. In our previous study, we found that knockdown of MIF by siRNA not only significantly reduced the expression of TNF-a，IL-6 and iNOS in LPS stimulated BV-2 microglia cells, but also significantly increased the expression of Arg1 in IL-4 stimulated BV-2 microglia cells. In addition, MIF inhibitor Z-590 significantly decreased the production of NO, TNF-a, IL-6, IL-1b, COX-2, iNOS as well as ROS in lipopolysaccharide (LPS)-activated BV-2 cells by inhibiting mitogen-activated protein kinase (MAPKs) signal pathway. Furthermore, we also found that Z-590 reduced cytotoxicity of activated microglia toward HT22 hippocampal cells in a microglia-conditional medium system. This study may suggest that MIF could be involved in the development of PD by regulation the phenotype of microglia, and further provide a new potential target for PD.

帕金森病是一种主要以黑质多巴胺神经元变性缺失为病理特征的神经退行性疾病。最近研究表明小胶质细胞介导的神经炎症也参与了帕金森病的发生发展，过度激活的小胶质细胞可以释放大量的促炎细胞因子，引发炎症级联反应，导致多巴胺神经元的损伤甚至死亡,加重PD的进程。巨噬细胞迁移抑制因子（MIF）在先天性免疫应答和适应性免疫应答反应中起着重要的调节作用，它可以促进其它炎症因子的释放，拮抗糖皮质激素的免疫抑制作用,被认为是一个强有力的抗炎作用靶点。我们前期实验结果发现当MIF被干扰后，不仅可以显著降低LPS诱导BV-2小胶质细胞激活释放的TNF-a，IL-6和iNOS，还可以上调IL-4诱导的Arg1的表达。此外，使用MIF小分子抑制剂也可以降低炎症因子的表达以及ROS释放，保护周围神经元。这些结果提示MIF可能通过调控小胶质细胞的表型进而参与帕金森病的发生发展，这也为治疗帕金森病提供了一个新的作用靶点。

巨噬细胞迁移抑制因子（MIF）是一种多功能促炎细胞因子，参与多种炎性疾病、免疫性疾病、肿瘤等，但其在帕金森病(PD)的作用及机制尚不明确。本次研究发现，MIF在帕金森患者和PD动物模型中表达升高。MIF基因沉默后可以显著降低LPS诱导BV-2小胶质细胞M1标记物iNOS、COX-2、IL-6、IL-1b、TNF-a表达，增加IL-4诱导小胶质细胞M2标记物Arg-1、MRC1、CD206、MGL-2的表达，这种调控作用可能是通过抑制NF-kB信号通路导致。在PD动物模型中，与野生型相比，MIF基因敲除小鼠的运动协调能力及多巴胺神经元显著提高，而小胶质细胞的激活水平下调。此外，利用小胶质细胞/神经元共培养技术同样发现，MIF基因沉默的小鼠可显著降低激活的小胶质细胞对多巴胺神经元的损伤。以上结果表明MIF可通过调控小胶质细胞的表型加重神经炎症进而影响PD的发生发展。提示以 MIF 为靶点,可能为帕金森药物的发现及生物治疗提供新策略。