中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (4): 856-862.doi: 10.4103/1673-5374.347739

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

剪接体GTP酶Eftud2可调节炎症反应中小胶质细胞的活化和极化

  

  • 出版日期:2023-04-15 发布日期:2022-10-29
  • 基金资助:
    国家自然科学基金项目(32171148,31770929,31522029);国家重点研发计划项目(2021ZD0202500,2021YFA1101801);北京市科委项目(Z181100001518001,Z161100000216154)

Spliceosomal GTPase Eftud2 regulates microglial activation and polarization

Guo-Chao Yang1, Yuan Shi2, Chao-Nan Fan2, Ying Li2, Meng-Qi Yuan3, Jie Pei4, Yan Wu2, Hai-Tao Wu1, 2, 5, *   

  1. 1School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China;  2Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China;  3Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, Hunan Province, China;  4School of Basic Medicine, Anhui Medical University, Hefei, Anhui Province, China;  5Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
  • Online:2023-04-15 Published:2022-10-29
  • Contact: Hai-Tao Wu, PhD, wuht@bmi.ac.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 32171148, 31770929, 31522029 (all to HTW); the National Key Research and Development Program of China, Nos. 2021ZD0202500, 2021YFA1101801 (both to HTW); and a grant from Beijing Commission of Science and Technology of China, Nos. Z181100001518001, Z161100000216154 (both to HTW). 

摘要:

剪接体组分延伸因子Tu GTP结合域蛋白 2(Eftud2)是一种剪接体GTP酶,可作为限制病毒感染的先天免疫调节剂。小胶质细胞是常驻的先天免疫细胞,也是中枢神经系统免疫反应的关键参与者,Eftud2是否参与小胶质细胞的作用尚不可知。实验首先通过免疫荧光染色和蛋白质印迹发现Eftud2在5xFAD 转基因小鼠模型的小胶质细胞中的表达持续上调。接下来,对CX3CR1-CreER; Eftud2flox/flox条件性敲除小鼠腹腔注射4OH-他莫昔芬,诱导获得小胶质细胞特异性Eftud2敲除小鼠模型,发现Eftud2缺失可导致大脑小胶质细胞异常增殖,并促进其抗炎表型的激活。进一步以特异性靶向Eftud2的小干扰RNA敲低BV2小胶质细胞中的Eftud2作为体外模型研究其作用机制,发现Eftud2介导的对炎症反应的小胶质细胞促炎/抗炎表型激活的调节可能依赖于核因子κB信号通路。综上表明Eftud2可在调节小胶质细胞极化和稳态方面起重要作用,且可能通过核因子κB通路起作用。

https://orcid.org/0000-0001-8437-3194 (Hai-Tao Wu)

关键词: 小胶质细胞, Eftud2, 剪接体GTP酶, 炎症, 核因子κB, BV2细胞, 脂多糖, 促炎表型, 抗炎表型, 阿尔茨海默病

Abstract: Elongation factor Tu GTP binding domain protein 2 (Eftud2) is a spliceosomal GTPase that serves as an innate immune modulator restricting virus infection. Microglia are the resident innate immune cells and the key players of immune response in the central nervous system. However, the role of Eftud2 in microglia has not been reported. In this study, we performed immunofluorescent staining and western blot assay and found that Eftud2 was upregulated in microglia of a 5xFAD transgenic mouse model of Alzheimer’s disease. Next, we generated an inducible microglia-specific Eftud2 conditional knockout mouse line (CX3CR1-CreER; Eftud2f/f cKO) via Cre/loxP recombination and found that Eftud2 deficiency resulted in abnormal proliferation and promoted anti-inflammatory phenotype activation of microglia. Furthermore, we knocked down Eftud2 in BV2 microglia with siRNA specifically targeting Eftud2 and found that Eftud2-mediated regulation of microglial proinflammatory/anti-inflammatory phenotype activation in response to inflammation might be dependent on the NF-κB signaling pathway. Our findings suggest that Eftud2 plays a key role in regulating microglial polarization and homeostasis possibly through the NF-κB signaling pathway.

Key words: Alzheimer’s disease, anti-inflammatory phenotype, BV2, Eftud2, inflammation, lipopolysaccharide, microglia, nuclear factor-kappaB, proinflammatory phenotype, spliceosomal GTPase