Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation-induced cell death
Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation-induced cell death
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小胶质细胞中 Nur77 的激活可减弱促炎介质的产生并保护多巴胺能神经元免受炎症诱导的细胞死亡
DOI：
10.1111/jnc.13907
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发表时间：
2017-02-01
影响因子：
4.7
通讯作者：
Zhen, Xue-Chu
中科院分区：
文献类型：
--
作者：
Liu, Tian-Ya;Yang, Xiao-Ying;Zhen, Xue-Chu
小胶质细胞介导的神经炎症在帕金森病（PD）的病理发展中起着关键作用。孤儿核受体Nur 77（Nur 77）在神经元中含量丰富，但其在小胶质细胞介导的神经炎症中的作用尚不清楚。本研究结果表明，在体外和实验性的1-甲基-4-苯基-1，2，3，6-四氢吡啶-PD小鼠模型中，小胶质细胞在脂多糖（LPS）刺激下Nur 77的表达降低，同时伴随着小胶质细胞的激活。Nur 77过表达或应用Nur 77激动剂胞孢素B抑制了激活的小胶质细胞中促炎基因的表达，如诱导型一氧化氮NOS、环氧合酶-2、IL-1 β和肿瘤坏死因子-α，而沉默的Nur 77则加剧了小胶质细胞中的炎症反应。此外，Nur 77的激活抑制了LPS诱导的NF-κ B的激活，这部分依赖于p38 MAPK活性，因为SB 203580抑制p38 MAPK消除了小胶质细胞中LPS激活的NF-κ B。另一方面，抑制p38 MAPK减弱LPS诱导的Nur 77减少。此外，在小胶质细胞条件培养基系统中，Nur 77改善了对MN 9D多巴胺能细胞的细胞毒性。最后，胞孢酮B减弱了1-甲基-4-苯基-1，2，3，6-四氢吡啶-PD小鼠模型的黑质旁核（SNpc）中小胶质细胞活化和多巴胺能神经元的损失。总之，这些发现揭示了Nur 77是与小胶质细胞介导的多巴胺能神经毒性相关的小胶质细胞功能的重要调节剂的第一个证据，因此Nur 77的调节可能代表治疗神经退行性疾病的潜在新靶点。
Microglia-mediated neuroinflammation plays a critical role in the pathological development of Parkinson's disease (PD). Orphan nuclear receptor Nur77 (Nur77) is abundant in neurons, while its role in microglia-mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied by microglia activation in response to lipopolysaccharide (LPS) in vitro and in experimental 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine-PD mouse model. Nur77 over-expression or application of Nur77 agonist cytosporone B suppressed the expression of proinflammatory genes, such as inducible nitric oxide NOS, cyclooxygenase-2, IL-1 beta, and tumor necrosis factor-alpha in the activated microglia, while silenced Nur77 exaggerated the inflammatory responses in microglia. Moreover, activation of Nur77 suppressed the LPS-induced NF-kappa B activation which was partly dependent on p38 MAPK activity, since inhibition of p38 MAPK by SB203580 abolished the LPSactivated NF-kappa B in microglia. On the other hand, inhibition of p38 MAPK attenuated LPS-induced Nur77 reduction. Furthermore, in a microglia-conditioned cultured media system, Nur77 ameliorated the cytotoxicity to MN9D dopaminergic cells. Lastly, cytosporone B attenuated microglia activation and loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Taken together, these findings revealed the first evidence that Nur77 was an important modulator in microglia function that associated with microglia-mediated dopaminergic neurotoxicity, and thus modulation of Nur77 may represent a potential novel target for treatment for neurodegenerative disease.