Glial activation involvement in neuronal death by Japanese encephalitis virus infection
Glial activation involvement in neuronal death by Japanese encephalitis virus infection
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DOI：
10.1099/vir.0.013565-0
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发表时间：
2010-04-01
影响因子：
3.8
通讯作者：
Chen, Jian-Hong
中科院分区：
文献类型：
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作者：
Chen, Chun-Jung;Ou, Yen-Chuan;Chen, Jian-Hong
日本脑炎的特点是严重的神经元破坏/功能障碍和伴随的小胶质细胞增多症/星形胶质细胞增多症。虽然在乙型脑炎病毒(JEV)诱导的乙型脑炎中观察到胶质细胞的大量激活，但JEV感染后星形胶质细胞和小胶质细胞激活的炎症反应和后果尚不完全清楚。在本研究中，JEV感染培养的神经元/神经胶质细胞导致神经元死亡和胶质细胞激活，表现为形态改变，细胞增殖增加，肿瘤坏死因子(TNF)-α，白介素1-β(IL-1β)，IL-6和RANTES(激活后调节，正常T细胞表达和分泌)的产生增加。复制能力强的乙型脑炎病毒引起所有的神经胶质反应和神经毒性。然而，无复制能力的JEV失去了这些能力，除了改变小胶质细胞形态的能力。激活的胶质细胞造成的旁观者损伤也是JEV相关神经毒性的原因之一。乙脑病毒感染后，小胶质细胞形态发生改变，细胞增殖增加，肿瘤坏死因子-α、IL-1β、IL-6和RANTES表达增加。相反，JEV感染的星形胶质细胞表达IL-6和RANTES，但未见明显的形态变化、增殖和肿瘤坏死因子-α/IL-1β的表达。感染乙脑病毒的小胶质细胞的培养上清液，而不是感染乙脑病毒的星形胶质细胞的培养上清液，可诱导胶质细胞激活并引发神经元死亡。抗体中和研究表明，激活的小胶质细胞释放的TNF-α和IL-1β，而不是RANTES或IL-6，似乎在乙型脑炎病毒相关的神经毒性中起作用。结论：乙型脑炎病毒感染后，神经元死亡伴随着小胶质细胞和星形胶质细胞的增多，并且JEV激活的小胶质细胞而不是JEV激活的星形胶质细胞释放的神经毒性介质具有放大小胶质细胞反应和导致神经元死亡的能力。
Japanese encephalitis is characterized by profound neuronal destruction/dysfunction and concomitant microgliosis/astrogliosis. Although substantial activation of glia is observed in Japanese encephalitis virus (JEV)-induced Japanese encephalitis, the inflammatory responses and consequences of astrocytes and microglial activation after JEV infection are not fully understood. In this study, infection of cultured neurons/glia with JEV caused neuronal death and glial activation, as evidenced by morphological transformation, increased cell proliferation and elevated tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6 and RANTES (regulated upon activation, normal T-cell expressed and secreted) production. Replication-competent JEV caused all glial responses and neurotoxicity. However, replication-incompetent JEV lost these abilities, except for the ability to change microglial morphology. The bystander damage caused by activated glia also contributed to JEV-associated neurotoxicity. Microglia underwent morphological changes, increased cell proliferation and elevated TNF-alpha, IL-1 beta, IL-6 and RANTES expression in response to JEV infection. In contrast, IL-6 and RANTES expression, but no apparent morphological changes, proliferation or TNF-alpha/IL-1 beta expression, was demonstrated in JEV-infected astrocytes. Supernatants of JEV-infected microglia, but not JEV-infected astrocytes, induced glial activation and triggered neuronal death. Antibody neutralization studies revealed that TNF-alpha and IL-1 beta, but not RANTES or IL-6, released by activated microglia appeared to play roles in JEV-associated neurotoxicity. In conclusion, following JEV infection, neuronal death was accompanied by concomitant microgliosis and astrogliosis, and neurotoxic mediators released by JEV-activated microglia, rather than by JEV-activated astrocytes, had the ability to amplify the microglial response and cause neuronal death.