Ni Chen, Wang Chunhui, Zhang Jingjing, Qu Liwei, Liu Xiaoman, Lu Yu, Yang Wei, Deng Jingjing, Lorenz Dorothea, Gao Pan, Meng Qinghong, Yan Xiyun, Blasig Ingolf E, Qin Zhihai
Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of the Chinese Academy of Sciences, Beijing, China.
Affiliated Hospital of Guangdong Medical College, Zhanjiang, China; Leibniz Institute for Molecular Pharmacology, Berlin-Buch, Germany.
Am J Pathol. 2014 Dec;184(12):3308-20. doi: 10.1016/j.ajpath.2014.08.019. Epub 2014 Oct 7.
The function of blood-brain barrier is often disrupted during the progression of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the molecular mechanism of blood-brain barrier modulation during neuroinflammation remains unclear. Herein, we show that the expression of interferon-γ (IFNγ) receptor on endothelial cells (ECs) protected mice from the brain inflammation during EAE. IFNγ stabilized the integrity of the cerebral endothelium and prevented the infiltration of leukocytes into the brain. Further analysis revealed that IFNγ increased the expression of tight junction proteins zonula occludens protein 1 and occludin, as well as membranous distribution of claudin-5, in brain ECs. Silencing claudin-5 abolished the IFNγ-mediated improvement of EC integrity. Taken together, our results show that IFNγ, a pleiotropic proinflammatory cytokine, stabilizes blood-brain barrier integrity and, therefore, prevents brain inflammation during EAE.
在多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎（EAE）的进展过程中，血脑屏障的功能常常受到破坏。然而，神经炎症期间血脑屏障调节的分子机制仍不清楚。在此，我们表明内皮细胞（ECs）上干扰素-γ（IFNγ）受体的表达可保护小鼠在EAE期间免受脑部炎症。IFNγ稳定了脑内皮的完整性，并防止白细胞浸润到大脑中。进一步分析表明，IFNγ增加了脑ECs中紧密连接蛋白闭合蛋白1和闭合蛋白的表达，以及claudin-5的膜分布。沉默claudin-5消除了IFNγ介导的EC完整性改善。综上所述，我们的结果表明，IFNγ作为一种多效性促炎细胞因子，可稳定血脑屏障的完整性，从而在EAE期间预防脑部炎症。
