Abstract：
Parkinson\'s disease (PD) is a severe neurodegenerative disease associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although its pathogenesis remains unclear, microglia-mediated neuroinflammation significantly contributes to the development of PD. Here we showed that the sine oculis homeobox (SIX) homologue family transcription factors SIX2 exerted significant effects on neuroinflammation. The SIX2 protein, which is silenced during development, was reactivated in lipopolysaccharide (LPS)-treated microglia. The reactivated SIX2 in microglia mitigated the LPS induced inflammatory effects, and then reduced the toxic effect of conditioned media (CM) of microglia on co-cultured MES23.5 DA cells. Using the LPS-stimulated Cx3cr1-CreERT2 mouse model, we also demonstrated that the highly-expressed SIX2 in microglia obviously attenuated neuroinflammation and protected the DA neurons in SN. Further RNA-Seq analysis on the inflammatory activated microglia revealed that the SIX2 exerted these effects via up-regulating the FXYD domain containing ion transport regulator 2 (FXYD2). Taken together, our study demonstrated that SIX2 was an endogenous anti-inflammatory factor in microglia, and it exerted anti-neuroinflammatory effects by regulating the expression of FXYD2, which provides new ideas for anti-neuroinflammation in PD.
摘要：
帕金森病（PD）是一种严重的神经退行性疾病，与黑质（SN）中多巴胺能（DA）神经元的丢失有关。虽然其发病机制尚不清楚,小胶质细胞介导的神经炎症显著促进PD的发展。在这里，我们表明sineoculishomeobox（SIX）同源家族转录因子SIX2对神经炎症具有显着影响。SIX2蛋白，在开发过程中被沉默，在脂多糖（LPS）处理的小胶质细胞中重新激活。小胶质细胞中重新激活的SIX2减轻了LPS诱导的炎症作用，然后降低了小胶质细胞条件培养基（CM）对共培养的MES23.5DA细胞的毒性作用。使用LPS刺激的Cx3cr1-CreERT2小鼠模型，我们还证明，在小胶质细胞中高表达的SIX2明显减轻了神经炎症并保护了SN中的DA神经元。对炎性活化的小胶质细胞的进一步RNA-Seq分析显示,SIX2通过上调含FXYD结构域的离子转运调节因子2(FXYD2)发挥这些作用。一起来看,我们的研究表明，SIX2是小胶质细胞的内源性抗炎因子，并通过调节FXYD2的表达发挥抗神经炎症作用,为PD的抗神经炎症提供了新思路。
