DOI: 10.57760/sciencedb.25874
title: VEGFR-3 deficiency in astrocytes exacerbates the Japanese encephalitis virus infection-induced neuroinflammatory response in the brains of mice
title: 星形胶质细胞中VEGFR-3缺陷加剧小鼠脑内日本乙型脑炎病毒感染诱导的神经炎症反应

description: Japanese encephalitis virus (JEV) is a kind of neurotropic pathogens 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 mice with deletion of the ligand-binding domain of VEGFR-3 in astrocytes. 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.
description: Japanese encephalitis virus (JEV) is a kind of neurotropic pathogens 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 mice with deletion of the ligand-binding domain of VEGFR-3 in astrocytes. 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.