Nucleotide-Binding Oligomerization Domain 1 (NOD1) Positively Regulates microglia-driven inflammatory response during Pseudorabies Virus Infection

The main cause of viral encephalitis is that the virus invades the central nervous system (CNS) and causes neuroinflammation, which poses a serious threat to the world's public health. Microgliaare CNS-resident macrophages that playanimportantroleinneuroinflammation and thus often identified as target of choice for the prevention or treatment of viral encephalitis. Nucleotide-binding oligomerization domain 1 (NOD1) is a type of pattern recognition receptor and has been associated with many inflammatory diseases in humans. Here, we used pseudorabiesvirus (PRV) as a model to examine the regulation of microglia responses during viral encephalitis and discuss whether NOD1 suppressed neuroinflammation by regulating microglial activation. Cellular experiments indicated that microglia activation accompanying by cell migration, characteristic morphological changes, phagocytosis, inflammatory cytokine production and antigen presentation. We then investigated the effect of NOD1 on the PRV-induced microglia activation. Theresultsinvitro and in vivoshowedthat PRV infection upregulated the mRNA and protein expression of NOD1. Inhibition or overexpression of NOD1 can reduce or enhance the activation JNK and NF-?B signal pathway to regulate the microglia activation and inflammatory response induced by PRV. Overall design: Comparative gene expression profiling analysins of RNA-seq data for BV2 cells with or without PRV

病毒性脑炎的主要致病机制为病毒侵袭中枢神经系统（central nervous system, CNS）并引发神经炎症，对全球公共卫生构成严重威胁。小胶质细胞（microglia）是中枢神经系统驻留巨噬细胞，在神经炎症过程中发挥关键作用，因此常被选为病毒性脑炎防治的理想靶向靶点。核苷酸结合寡聚化结构域1（nucleotide-binding oligomerization domain 1, NOD1）属于一类模式识别受体，已被证实与人类多种炎症性疾病密切相关。本研究以伪狂犬病病毒（pseudorabies virus, PRV）为模型，探究病毒性脑炎进程中小胶质细胞的应答调控机制，并探讨NOD1是否通过调节小胶质细胞活化来抑制神经炎症。细胞实验结果显示，小胶质细胞活化伴随细胞迁移、特征性形态改变、吞噬作用、炎性细胞因子产生及抗原呈递等生物学过程。随后本研究考察了NOD1对PRV诱导的小胶质细胞活化的调控效应。体外与体内实验结果表明，PRV感染可上调NOD1的mRNA与蛋白表达水平。抑制或过表达NOD1，可分别降低或增强JNK与NF-κB信号通路的活化程度，从而调控PRV诱导的小胶质细胞活化与炎症应答。整体实验设计：对有无PRV感染的BV2细胞的RNA测序（RNA-seq）数据开展比较基因表达谱分析。