基于GR/GILZ轴研究青蒿琥酯调控糖皮质激素免疫抑制作用的分子机制

糖皮质激素(GCs)诱导的免疫抑制所致的二次感染严重限制其应用，其发生与糖皮质激素受体/糖皮质激素诱导的亮氨酸拉链蛋白(GR/GILZ)轴介导的基因效应密切相关。我们前期发现青蒿琥酯(AS)是一良好的双向免疫调节药，既保证GCs的疗效又减轻其免疫抑制。基于AS可提高GCs诱导的免疫抑制小鼠、巨噬细胞释放致炎细胞因子和清除细菌的能力，该作用与下调GILZ mRNA表达有关，生物信息学结果提示GRα、GILZ可能是AS的药靶，提出“在GCs诱导的免疫抑制情况下，AS通过与GRα和/或GILZ相互作用抑制GR/GILZ轴的表达和功能，从而增强细胞的自噬过程，发挥增强机体清除细菌能力的作用”的假设。本项目拟围绕GR/GILZ轴：首先在细胞层面明确AS对GR/GILZ轴的影响，然后明确二者与AS的相互作用及位点，最后在动物模型上验证。为阐明AS免疫调节作用的分子机制、发现新药靶及老药新用奠定基础。

Secondary infections caused by glucocorticoid (GCs)-induced immunosuppression seriously limit its application, and its occurrence is closely related to glucocorticoid receptor/glucocorticoid-induced leucine zipper protein (GR/GILZ) axis of GCs-mediated gene effect. Previously, we have found that artesunate (AS) is a good bidirectional immunomodulatory drug, and can ensure the efficacy of GCs and reduce its adverse reactions induced by GCs. AS can enhance the ability of GCs-induced immunosuppressive mice and macrophages to release inflammatory cytokines and clear bacteria, which is related to the down-regulation of GILZ mRNA expression. The results from bioinformatics suggest that GR and GILZ might be drug targets of AS. Therefore, we proposed the hypothesis that "During GCs-induced immunosuppression, AS inhibits the expression and function of GR/GILZ axis by interacting with GRα and/or GILZ, thus enhancing the autophagy process of cells, leading to the increased ability to clear bacteria". Herein, our project is intended to work around GR/GILZ axis: Firstly, the effect of AS on GR/GILZ axis is identified at the cellular level, then the interaction between the two and AS and the possible sites are identified, and finally the results are verified in animal models. The purpose of this project is to lay a foundation for elucidating the immunomodulatory mechanism of AS, discovering new drug target and repurposing of AS in the future.