He Wen, Zhao Zikai, Anees Awais, Li Yunchuan, Ashraf Usama, Chen Zheng, Song Yunfeng, Chen Huanchun, Cao Shengbo, Ye Jing
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural UniversityWuhan, China.
Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural UniversityWuhan, China.
Front Cell Infect Microbiol. 2017 Jun 21;7:271. doi: 10.3389/fcimb.2017.00271. eCollection 2017.
Japanese encephalitis virus (JEV) targets central nervous system, resulting in neuroinflammation with typical features of neuronal death along with hyper activation of glial cells. Exploring the mechanisms responsible for the JEV-caused inflammatory response remains a pivotal area of research. In the present study, we have explored the function of p21-activated kinase 4 (PAK4) in JEV-mediated inflammatory response in human astrocytes. The results showed that JEV infection enhances the phosphorylation of PAK4 in U251 cells and mouse brain. Knockdown of PAK4 resulted in decreased expression of inflammatory cytokines that include tumor necrosis factor alpha, interleukin-6, interleukin-1β, and chemokine (C-C motif) ligand 5 and interferon β upon JEV infection, suggesting that PAK4 signaling promotes JEV-mediated inflammation. In addition, we found that knockdown of PAK4 led to the inhibition of MAPK signaling including ERK, p38 MAPK and JNK, and also resulted in the reduced nuclear translocation of NF-κB and phosphorylation of AP-1. These results demonstrate that PAK4 signaling actively promotes JEV-mediated inflammation in human astrocytes via MAPK-NF-κB/AP-1 pathway, which will provide a new insight into the molecular mechanism of the JEV-induced inflammatory response.
日本脑炎病毒（JEV）靶向中枢神经系统，导致神经炎症，其典型特征为神经元死亡以及胶质细胞的过度激活。探索JEV引发炎症反应的机制仍然是一个关键的研究领域。在本研究中，我们探讨了p21激活激酶4（PAK4）在人星形胶质细胞中JEV介导的炎症反应中的作用。结果表明，JEV感染增强了U251细胞和小鼠脑中PAK4的磷酸化。敲低PAK4导致JEV感染后包括肿瘤坏死因子α、白细胞介素-6、白细胞介素-1β、趋化因子（C-C基序）配体5和干扰素β在内的炎性细胞因子表达降低，这表明PAK4信号传导促进JEV介导的炎症。此外，我们发现敲低PAK4导致包括ERK、p38丝裂原活化蛋白激酶（MAPK）和JNK在内的MAPK信号传导受到抑制，还导致核因子κB（NF-κB）的核转位减少和活化蛋白-1（AP-1）的磷酸化降低。这些结果表明，PAK4信号传导通过MAPK-NF-κB/AP-1途径积极促进人星形胶质细胞中JEV介导的炎症，这将为JEV诱导的炎症反应的分子机制提供新的见解。
