打开APP

Cell Death Differ:Jmjd3在小胶质细胞介导的神经炎症中的调控机制

  1. Jmjd3
  2. 小胶质细胞
  3. 神经炎症
  4. 调控机制

来源:中科院健康所 2013-11-15 19:20

近日,Cell Death and Differentiation 在线发表了中科院健康所最新研究成果,揭示Jmjd3在小胶质细胞介导的神经炎症中的分子学调控机制。

近日,国际生物医学学术期刊《细胞死亡及分化》(Cell Death and Differentiation)在线发表了中科院上海生科院/上海交大医学院健康科学研究所乐卫东研究组的最新研究成果Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease,揭示Jmjd3在小胶质细胞介导的神经炎症中的分子学调控机制。

帕金森病(Parkinson’s Disease)是一种常见的中老年人神经系统变性疾病,病理上的表现主要为黑质区多巴胺能神经元的丢失以及蛋白包涵小体的形成,一般认为,主要与年龄老化、遗传和环境等因素有关。小胶质细胞介导的神经炎症在帕金森病发生过程中发挥了重要的作用,控制着多巴胺能神经元的生存和死亡。

在此项研究中,博士研究生唐宇在乐卫东研究员的指导下,发现小胶质细胞具有不同功能的极化表型:具有神经毒性的M1型和具有神经营养和神经保护的M2型,而这种表型极化由组蛋白H3K27me3去甲基化酶Jmjd3所调控。在小胶质细胞中敲低Jmjd3后,M2型marker(Arg1,CD206)的表达受到抑制,而M1型marker(iNOS,IL-1β,IL-6)表达相应上升,这也导致了与其共培养的神经元大量死亡。在构建的神经毒素MPTP注射的小鼠模型中,在黑质敲低Jmjd3后,多巴胺能神经元死亡明显加剧。另外,他们还发现老年鼠中脑的M1型marker和H3K27me3的水平较高,而M2型marker以及Jmjd3表达下降了,提示老化对小胶质细胞的表型极化发挥了重要作用。

该项研究阐述了小胶质细胞在中脑黑质区构筑了多巴胺能神经元生存的微环境,通过极化成具有不同功能的表型,控制着神经元的死亡,使神经元-胶质细胞的微环境达到平衡。而环境毒素,UPS损伤,以及年龄老化都可能打破这种平衡,从而加剧神经元丢失和帕金森病的发生。这为小胶质细胞介导的神经炎症在帕金森病中的致病机理提供了新的分子基础,为治疗帕金森病提供了新的思路。

此课题研究得到了国家自然科学基金委和中国科学院等经费资助。(生物谷Bioon.com)

生物谷推荐的英文摘要

Cell Death and Differentiation       doi:10.1038/cdd.2013.159

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

Y Tang, T Li, J Li, J Yang, H Liu, X J Zhang and W Le

Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either detrimental or beneficial effects in the central nervous system (CNS). Harnessing the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of Parkinson’s disease (PD). However, the epigenetic mechanism that regulates microglia polarization remains elusive. Here, we reported that histone H3K27me3 demethylase Jumonji domain containing 3 (Jmjd3) was essential for M2 microglia polarization. Suppression of Jmjd3 in N9 microglia inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, which led to extensive neuron death in vitro. We also observed that the suppression of Jmjd3 in the substantia nigra (SN) in vivo dramatically caused microglial overactivation and exacerbated dopamine (DA) neuron death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD. Moreover, we showed that the Jmjd3 level was lower in the midbrain of aged mice, which was accompanied by an elevated level of H3K27me3 and an increased ratio of M1 to M2 markers, suggesting that aging is an important factor in switching the microglia phenotypes. Overall, our studies indicate that Jmjd3 is able to enhance the polarization of M2 microglia by modifying histone H3K27me3, and therefore it has a pivotal role in the switch of microglia phenotypes that may contribute to the immune pathogenesis of PD.

版权声明 本网站所有注明“来源:生物谷”或“来源:bioon”的文字、图片和音视频资料,版权均属于生物谷网站所有。非经授权,任何媒体、网站或个人不得转载,否则将追究法律责任。取得书面授权转载时,须注明“来源:生物谷”。其它来源的文章系转载文章,本网所有转载文章系出于传递更多信息之目的,转载内容不代表本站立场。不希望被转载的媒体或个人可与我们联系,我们将立即进行删除处理。

87%用户都在用生物谷APP 随时阅读、评论、分享交流 请扫描二维码下载->