HnRNP A2/B1激活STING-TBK1-Ⅰ型干扰素通路在系统性红斑狼疮中的机制研究

系统性红斑狼疮（SLE）是一类常见的自身免疫病。树突状细胞（DC）活化，释放Ⅰ型干扰素（Ⅰ-IFN）增多在SLE中发挥重要作用。申请者前期也发现SLE患者游离DNA及Ⅰ-IFN增多。DNA是DC分泌Ⅰ-IFN重要的诱导剂，但DNA诱导DC分泌Ⅰ-IFN的机制仍不完全明确。最新发现，异质性胞核核糖核蛋白A2B1(hnRNP A2/B1)能结合DNA，激活Ⅰ-IFN通路。申请者首次发现SLE患者外周血DC中hnRNP A2/B1高表达。我们提出假说“DNA通过结合DC中hnRNP A2/B1，激活STING-TBK1-Ⅰ-IFN通路，参与SLE发生发展”。本课题拟通过体外试验探讨DNA能否激活DC中hnRNP A2/B1-Ⅰ-IFN通路；动物试验阐明抑制hnRNP A2/B1表达对Ⅰ-IFN及狼疮小鼠病情的影响；并在临床上验证hnRNP A2/B1与狼疮病情的相关性，为SLE的治疗提供新靶点。

Systemic lupus erythematosus (SLE) is a common type of autoimmune disease. The activation of dendritic cells (DCs) and the increased release of type Ⅰ interferon (Ⅰ-IFN) play an important role in the pathogenesis and progression of SLE. DNA can induce DCs to secrete Ⅰ-IFN and we also found that DNA and I-IFN were increased in the peripheral blood of SLE. However, the mechanism by which DNA induces DCs to secrete I-IFN is still not fully clear. Recently, it was found that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNP A2/B1) could bind DNA and activate the I-IFN pathway. And we first found higher expression of hnRNP A2/B1 in peripheral blood DCs of SLE patients. Therefore, we propose a hypothesis that DNA can activate the STING-TBK1-I-IFN pathway by binding hnRNP A2/B1 in DCs, which plays a role in the development of SLE. To verify this hypothesis, we aim to first investigate whether DNA can activate the hnRNP A2/B1-Ⅰ-IFN pathway in DCs. Secondly, we will clarify the effect of inhibiting the expression of hnRNP A2/B1 on the I-IFN pathway and the condition of lupus mice. Finally, we will explore the correlation of hnRNP A2/B1 expression in DCs with the condition of lupus, which may provide a new therapeutic target for SLE.