linc0597/miR-92a介导Fractalkine调控Th17/Treg细胞在系统性红斑狼疮发病中的作用及其机制研究

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the imbalance of Th17/Treg cells. It was proved that noncoding RNAs involved in the pathogenesis of SLE, the expression of linc0597 increased and the expression of miR-92a decreased in the peripheral blood of SLE patients. Our previous study confirmed that chemokine Fractalkine (FKN) was involved in the pathogenesis of SLE; FKN can be involved in the regulation of SLE Th17/Treg cells; After knockout of FKN gene, expression of linc0597 was downregulated, MAPK signaling pathway was abnormal and transcription was negatively regulated, which indicates that linc0597 can interact with FKN. The prediction analysis showed that there are binding sites between miR-92a and linc0597 as well as FKN. Therefore, it is conjectured that linc0597 may mediate the regulation of FKN in Th17/Treg cells through competitive inhibition of miR-92a. In this study, we will highlight the regulatory role of FKN on Th17/Treg cells mediated by linc0597/miR-92a in the pathogenesis of systemic lupus erythematosus and its mechanisms through in vivo and in vitro experiments, and then provide theoretical and experimental basis for elucidating the pathogenesis of SLE.

系统性红斑狼疮（SLE）是一种以Th17/Treg细胞失衡为主要免疫学表现的自身免疫性疾病。研究证实非编码RNA参与其中，SLE患者外周血中linc0597表达增加，而miR-92a表达下调。项目组证实趋化因子Fractalkine（FKN）参与了SLE发病机理；FKN可调控狼疮鼠Th17/Treg细胞；敲除细胞FKN基因后linc0597表达明显下调、MAPK信号通路异常、转录负调节，表明linc0597与FKN存在相互作用。预测分析显示miR-92a与linc0597及FKN均存在结合位点。推测linc0597可能通过竞争性抑制miR-92a介导FKN参与的Th17/Treg细胞调控。本研究以此为切入点，通过体内外实验研究linc0597/miR-92a介导FKN调控Th17/Treg细胞在SLE发病中的作用及其转录和MAPK信号机制，为阐明SLE的发病机制提供理论依据和实验基础。

系统性红斑狼疮（SLE）是一种多器官受累的自身免疫性疾病。已有多项研究证实多种lncRNA在自身免疫性疾病发生和发展中发挥着重要作用。而目前关于lncRNA SOX2-OT和HOXA11-AS在SLE中的研究尚未见报道，有必要进一步研究。本研究发现与正常对照组相比，狼疮患者PBMCs中SOX2-OT表达显著下调；未治疗组狼疮患者SOX2-OT表达水平低于治疗组；活动组狼疮患者SOX2-OT表达水平低于稳定组SOX2-OT表达水平，提示低表达的SOX2-OT可能作为诊断狼疮的生物标志物。狼疮患者PBMCs中SOX2-OT表达水平与SLEDAI评分呈负相关，与C3、C4呈正相关，提示低表达的SOX2-OT可能作为评估LN疾病活动的生物标记物。在狼疮病人血液和狼疮小鼠肾组织中HOXA11-OS和自噬标志物明显上调，HOXA11-AS通过miR-124-3P/Cyr61轴参与调节细胞自噬进而影响狼疮性肾炎的发生发展。靶向抑制Cyr61的活性，可通过逆转HOXA11-AS异常表达所致的异常自噬，为狼疮性肾炎临床靶向治疗提供新策略，具有一定的理论意义和应用价值。