猪链球菌2型通过诱导IFN-γ促进脑微血管内皮细胞自噬破坏血脑屏障完整性  

Stre ptococcus suis type 2 promotes autophagy of brain microvascular endothelial cells by inducing IFN-γ to destroy the integrity of the blood-brain barrier

作　　者：刘嘉楠 贾丽 姜合祥 吴桐 李扬 雷连成 LIU Jian-an;JIA Li;JIANG He-xiang;WU Tong;LI Yang;LEI Lian-cheng(College of Veterinary Medicine,Jilin University,Changchun 130062,China;College of Nursing,Jilin University,Changchun 130062,China;College of Animal Science,Yangtze University,Jingzhou,Hubei 434023,China)

机构地区：[1]吉林大学动物医学学院,吉林长春130062 [2]吉林大学护理学院,吉林长春130062 [3]长江大学动物科学学院,湖北荆州434023

出　　处：《中国兽医学报》2020年第12期2320-2326,共7页Chinese Journal of Veterinary Science

基　　金：国家重点研发计划资助项目(2017YFD0500204);国家自然科学基金面上资助项目(31772715);吉林省教育厅科学研究规划资助项目(JJKH20201044KJ)。

摘　　要：猪链球菌2型(Streptococcus suis type 2,SS2)是一种能够引起猪和人类脑膜炎的人畜共患病原菌,其破坏血脑屏障(BBB)的免疫学致病机制仍知之甚少。本研究通过构建仔猪脑组织切片感染模型和原代猪脑微血管内皮细胞和星形胶质细胞(PBMEC/AC)共培养BBB感染模型,探讨SS2感染对BBB通透性的影响。结果显示,脑组织切片和双细胞共培养BBB模型感染SS2后,IFN-γ均显著高表达。在组织切片培养液添加IFN-γ,可见脑组织出现自噬;在双细胞共培养BBB模型中添加IFN-γ后发现跨内皮电阻(TEER)值显著降低,表明BBB通透性降低,IFN-γ破坏了BBB完整性。进一步研究发现,IFN-γ能够促进PBMEC高表达自噬信号分子ULK1、Beclin1、LC3-Ⅰ和LC3-Ⅱ,诱导PBMECs的自噬。添加精氨酸可以降低IFN-γ诱导的自噬并恢复BBB细胞模型的致密性。研究表明,IFN-γ可能通过诱导PBMEC自噬破坏BBB的完整性,增强屏障的通透性,从而促进细菌进入脑组织。本研究从免疫学角度为SS2脑膜炎的发生提供了新机制。Streptococcus suis type 2(SS2)is a zoonotic pathogen that can cause meningitis in pigs and humans.The immunological pathogenesis of its destruction on the blood-brain barrier(BBB)is still poorly understood.In this study,a SS2 infection model of the piglet brain tissue section and the BBB model of co-culture of piglet brain microvascular endothelial cells and astrocytes(PBMEC/AC)were constructed to explore the effect of SS2 infection on BBB permeability.The results showed that,after the brain tissue and the two cells co-culture BBB model were infected with SS2,IFN-γ was significantly high expressed.The addition of IFN-γ to the culture medium of tissue sections caused autophagy in brain tissue.After adding IFN-γ to the two cells co-culture BBB model,it is found that the value of transendothelial resistance(TEER)is significantly reduced,indicating that the permeability of BBB is reduced,and IFN-γ destroys the integrity of the BBB.Further studies revealed that IFN-γ was able to promote the high expression of autophagy signaling molecules ULK1,Beclin1,LC3-Ⅰ and LC3-Ⅱ in PBMECs,and it induced autophagy in PBMECs.Adding arginine could reduce the autophagy induced by IFN-γ and restored the compactness of the BBB cell model.This study suggests that IFN-γ may destroy the integrity of BBB by inducing PBMEC autophagy,enhance the permeability of BBB,and promote the entry of bacteria into brain tissue.This study provides a novel mechanism for the occurrence of SS2 meningitis from an immunological perspective.

关 键 词：猪链球菌2型 脑膜炎 IFN-Γ 血脑屏障(BBB) 自噬 

分 类 号：S852.611[农业科学—基础兽医学]