Nuclear receptor‐related 1 protein (NURR1) is essential for the development and maintenance of midbrain dopaminergic (DAergic) neurons. NURR1 also protects DAergic neurons against neuroinflammation. However, it remains to be determined to what extent does NURR1 exerts its protective function through acting autonomously in the microglia. Using Cre/lox gene targeting system, we deleted Nurr1 in the microglia of Nurr1 ^Cd11bcre conditional knockout (cKO) mice. The Nurr1 ^Cd11bcre cKO mice displayed age‐dependent motor abnormalities and increased microglial activation, but with no obvious DAergic neurodegeneration. To boost the inflammatory injury, we systemically administered endotoxin lipopolysaccharide (LPS) to Nurr1 ^Cd11bcre mice. As expected, LPS treatment exacerbated the motor phenotypes and inflammatory reactions in Nurr1 ^Cd11bcre cKO mice. More importantly, LPS administration caused DAergic neuron loss and α‐synuclein aggregation, two pathological hallmarks of Parkinson's disease (PD). Therefore, our findings provide in vivo evidence supporting a critical protective role of NURR1 in the microglia against inflammation‐induced degeneration of DAergic neurons in PD.

中文翻译：

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Nurr1Cd11bcre 条件性敲除小鼠对黑质纹状体多巴胺能神经元表现出炎症损伤。

核受体相关 1 蛋白 (NURR1) 对于中脑多巴胺能 (DAergic) 神经元的发育和维持至关重要。NURR1 还保护 DAergic 神经元免受神经炎症。然而，NURR1通过在小胶质细胞中自主作用发挥其保护功能的程度仍有待确定。使用 Cre/lox 基因靶向系统，我们删除了Nurr1 ^Cd11bcre条件性敲除 (cKO) 小鼠小胶质细胞中的Nurr1 。Nurr1 ^Cd11bcre cKO 小鼠表现出年龄依赖性运动异常和小胶质细胞活化增加，但没有明显的 DAergic 神经变性。为了促进炎症损伤，我们将内毒素脂多糖 (LPS) 系统性地施用于Nurr1^Cd11bcre小鼠。正如预期的那样，LPS 治疗加剧了Nurr1 ^Cd11bcre cKO 小鼠的运动表型和炎症反应。更重要的是，LPS 给药导致 DAergic 神经元丢失和 α-突触核蛋白聚集，这是帕金森病 (PD) 的两个病理特征。因此，我们的研究结果提供了体内证据，支持 NURR1 在小胶质细胞中对炎症诱导的 PD 中 DAergic 神经元的退化具有关键保护作用。