Year: 2025
Type: article
Abstract: Japanese encephalitis virus (JEV) is a neurotropic pathogen with high sensitivity and extensive replication in neurons, which leads to widespread neural damage and inflammation within the central nervous system (CNS), thereby contributing to high disability and mortality rates. Vascular endothelial growth factor receptor 3 (VEGFR-3), a receptor tyrosine kinase encoded by the FLT4 gene, plays an essential role in regulating the vascular system, especially in the development and maintenance of the lymphatic system. Although VEGFR-3 expressed in macrophages has been shown to suppress bacterial sepsis and neuroinflammation, its function in astrocytes during JEV infection remains unclear. To investigate this, we generated VEGFR-3 conditional knockout (deletion of the ligand binding domain in astrocytes) mice. VEGFR-3 deficiency in astrocytes led to the upregulated transcription of inflammatory genes and the increased viral load in the brains of JEV-infected mice, ultimately reducing their survival rate. We also observed elevated expression of inflammatory cytokines and chemokines in the brains of JEV-infected mice with VEGFR-3 deficiency in astrocytes. In vitro experiments further demonstrated that chemical inhibition of VEGFR-3 intracellular kinase activity enhanced the expression of inflammatory cytokine genes in a JEV-infected astrocyte cell line. Collectively, our results demonstrate that VEGFR-3 negatively regulates astrocyte-mediated neuroinflammation during JEV infection.
Source: 动物学研究
Authors: Wang Xi-Lin, 上海大学医学院, 生命科学学院, 上海 200444, 中国, Zhao Qi, Liu Hong-Yang, Dai Yong-Sheng, Han Ming-Shun, Li Xiao-Jing, Li Feng, Ye Jing, Cao Sheng-Bo, Qi Lin-Lin, Wei Bin, 中国科学院生物化学与细胞生物学研究所细胞生物学国家重点实验室, 分子细胞科学越中心, 中国科学院大学, 上海 200031, 中国, 复旦大学医学神经生物学国家重点实验室, 脑科学前沿科学中心, 上海 200433, 中国, 武汉病毒研究所病毒学国家重点实验室, 中国科学院大学, 湖北 武汉 430071, 中国, 华中农业大学农业微生物学国家重点实验室, 湖北 武汉 430070, 中国
Institutions: Shanghai University, Chinese Academy of Sciences, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, State Key Laboratory of Cell Biology, Fudan University, State Key Laboratory of Medical Neurobiology, Frontiers Center for Brain Science of the Ministry of Education, Wuhan Institute of Virology, State Key Laboratory of Virology, Huazhong Agricultural University, State Key Laboratory of Agricultural Microbiology
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: diamond
Award: G8147208388
OpenAlex ID: W4412682252