Enterovirus 71 infection caused neuronal cell death and cytokine expression in cultured rat neural cells
Enterovirus 71 infection caused neuronal cell death and cytokine expression in cultured rat neural cells
复制标题
DOI：
10.1002/iub.1434
复制
发表时间：
2015-10-01
期刊：
影响因子：
4.6
通讯作者：
Chen, Chun-Jung
中科院分区：
文献类型：
--
作者：
Chang, Cheng-Yi;Li, Jian-Ri;Chen, Chun-Jung
致死性肠道病毒71型（EV 71）病例与中枢神经系统感染有关，其特征为炎性细胞浸润和活化、细胞因子过度产生和神经元细胞死亡。虽然已经在神经元和神经胶质中检测到EV 71抗原，但EV 71相关神经炎症和神经元细胞死亡的分子机制尚未完全了解。使用培养的啮齿动物神经细胞模型，我们发现EV 71感染优先引起神经元细胞死亡，而不是脑驻留免疫细胞星形胶质细胞和小胶质细胞。神经元、星形胶质细胞和小胶质细胞通过释放不同的细胞因子谱对EV 71感染作出反应，所述细胞因子包括一氧化氮（NO）、肿瘤坏死因子-（TNF-α）、白细胞介素（IL）-1、调节正常T细胞表达和分泌的活化（RANTES）和谷氨酸。EV 71感染诱导的神经元细胞死亡与NO、TNF-α、IL-1和谷氨酸的产生以及小胶质细胞的活化密切相关。外源性添加研究进一步证明了NO、TNF-α、IL-1和谷氨酸的神经毒性潜力。EV 71感染诱导的细胞因子表达伴随着蛋白酪氨酸磷酸化、促分裂原活化蛋白激酶（MAPK）和NF-B的活化。有趣的是，EV 71易感性伴随着感染升高的神经元人清道夫受体B类成员2在培养的神经细胞中的表达，具有年龄依赖性。生化和药理学研究表明，EV 71感染后，小胶质细胞和伴随的细胞因子在触发涉及酪氨酸激酶/MAPKs/NF-B信号级联的神经元旁观者损伤中发挥积极作用。这些数据表明，由活化的胶质细胞特别是小胶质细胞引起的旁观者损伤可能是EV 71相关神经元细胞死亡的另一种机制。然而，其临床意义和影响需要进一步研究。(c)2015 IUBMB Life，67（10）：789-800，2015
Fatal enterovirus type-71 (EV71) cases are associated with central nervous system infection characterized by inflammatory cell infiltration and activation, cytokine overproduction, and neuronal cell death. Although EV71 antigen has been detected in neurons and glia, the molecular mechanisms underlying EV71-associated neuroinflammation and neuronal cell death are not fully understood. Using cultured rodent neural cell models, we found that EV71 infection preferentially caused cell death in neurons but not brain-resident immune cells astrocytes and microglia. Neurons, astrocytes, and microglia responded to EV71 infection by releasing distinct profiles of cytokines, including nitric oxide (NO), tumor necrosis factor- (TNF-), interleukin (IL)-1, regulated on activation normal T cell expressed and secreted (RANTES), and glutamate. EV71 infection-induced neuronal cell death correlated well with the elevated production of NO, TNF-, IL-1, and glutamate as well as activation of microglia. Exogenous addition studies further demonstrated the neurotoxic potential of NO, TNF-, IL-1, and glutamate. EV71 infection-induced cytokine expression was accompanied by activation of protein tyrosine phosphorylation, mitogen-activated protein kinases (MAPKs), and NF-B. Intriguingly, EV71 susceptibility was accompanied by infection-elevated neuronal human scavenger receptor class B member 2 expression in cultured neural cells with age-dependent manner. Biochemical and pharmacological studies revealed that after EV71 infection, microglia and accompanied cytokines play an active role in triggering bystander damage to neurons involving the tyrosine kinase/MAPKs/NF-B signaling cascade. These data suggest that bystander damage caused by activated glia particularly the microglia could be an alternative mechanism of EV71-associated neuronal cell death. However, its clinical importance and implication require further investigation. (c) 2015 IUBMB Life, 67(10):789-800, 2015