miR-181a诱导树突状细胞负向免疫调控在动脉粥样硬化中的意义与机制

Immune inflammtion response is critical for atherosclerosis. Dendritic cells (DC) initiate and modulate immune inflammation response. We have demonstrated that some risk factors of AS activate and propagate the immune inflammation response. We have also found that DC negatively modulate the immune inflammation response with undetermined mechanisms. miRNAs regulate DC and are pathologically involved in AS. We have observed that miR-181a attenuated the ox-LDL-induced immune inflammation response by targeting the transcritpion of c-Fos. Additionally, JAK/STAT1 is critical for DC activation, and STAT1 has been reported to interact with c-Fos. We therfore hypothesize that miR-181a negatively modulates DC immune inflammation response by interefing JAK/STAT1-c-Fos-NF-KB pathway, so as to suppress the inflammation response of AS and to protect the aortic tissue. We firstly investigate the modulatory effects and mechanisms of miR-181a to DC; then, we analyze the protective effects of miR-181a to AS based on the atherosclerotic animal models and the deletion and replenish of DC. Finally, we investigate the clinical significance of miR-181a in coronary heart disease patients. Through this study, we want to demonstrate the DC-mediated negative modulation function in AS as well as the miRNA-mediated epigenetic mechanisms of AS.

免疫炎症反应是动脉硬化（atherosclerosis,AS）的关键机制，而且是复杂的免疫平衡过程。树突状细胞（dendritic cell, DC）启动炎症，同时也具有负向调控作用，维持免疫稳态，但调控机制不清。微小RNA (miRNAs) 调控DC并参与AS。我们发现miR-181a靶向抑制c-Fos以减轻氧化低密度脂蛋白诱导的DC炎症反应。JAK/STAT1为DC激活的关键通路，且STAT1与c-Fos相互作用并调控NF-KB。因而假说：miR-181a通过JAK/STAT1-c-Fos-NF-K以诱导DC负向调控，减轻炎症，保护动脉管壁。研究拟先确立miR-181a诱导DC负向调控效应和机制；再基于AS模型和DC缺失与回输等实验，确立miR-181a诱导DC负向免疫调控以保护AS的效应；并阐明其临床意义。通过本研究，揭示DC负向免疫调对AS的关键作用，并拓展AS表观遗传修饰机制。

我们研究发现miR-181a在高脂血症中的表达上调， miR-181a表达上调可降低DC的成熟度，从而减弱ox-LDL通过c-Fos通路对DC的的激活及促炎作用而导致的AS，这为miR-181a负向免疫调控高脂血症导致的AS提供了一条新的思路。另外，我们的研究还发现DC可通过分泌EXs这一Cell-Cell的mediator影响脂质代谢，及通过血管内皮细胞的促炎作用而促进动脉粥样硬化（AS）及调控心肌梗死后的心脏重构。小鼠MI后肝脏DC浸润增加,肝脏浸润的DC可分泌DEXs并通过MTOR-AMPK-SREBP通路影响脂质代谢，使血脂水平增高而促进AS发生，这是MI后促进AS的一项新的机制。成熟DC分泌的EXs可以促进内皮细胞炎症和AS，该作用是通过DC-EXs（DEXs）膜表面的TNF-α介导的NF-κB途径完成。同时，我们研究还发现小鼠MI后MI部位浸润的DC可通过分泌DEXs激活CD4 T细胞，并且通过体外注射MI-DEXs可显著改善小鼠MI后心脏功能。