cGAS/STING/IFN-Ⅰ信号通路介导内皮祖细胞对系统性红斑狼疮相关性动脉粥样硬化的保护作用  

The protective effect of cGAS/STING/IFN-Ⅰsignaling pathway mediating endothelial progenitor cells on atherosclerosis associated with systemic lupus erythematosus

作　　者：林秋玉 何思懿 刘玲娟 黄鹏[3,4] 张路 陶思思 徐志泉 任翼[6] 莫双红 李虹艾[1] 向伟 何小解 Lin Qiuyu;He Siyi;Liu Lingjuan;Huang Peng;Zhang Lu;Tao Sisi;Xu Zhiquan;Ren Yi;Mo Shuanghong;Li Hongai;Xiang Wei;He Xiaojie(Hainan Women and Children Medical Center,Haikou 571000,China;Department of Anesthesiology,Hainan Provincial People′s Hospital,Haikou 571000,China;Department of Pediatrics,The Second Xiangya Hospital,Central South University,Changsha 410011,China;Department of Pediatric Neurology,The Second Xiangya Hospital,Central South University,Changsha 410011,China;Changsha Maternal and Child Health Hospital,Hunan Normal University,Changsha 410007,China;Department of Pediatrics,Haikou Maternal and Child Health Hospital,Haikou 571000,China;Department of Pediatric Nephrology,The Second Xiangya Hospital,Central South University,Changsha 410011,China)

机构地区：[1]海南省妇女儿童医学中心,海口571000 [2]海南省人民医院麻醉科,海口571000 [3]中南大学湘雅二医院儿科,长沙410011 [4]中南大学湘雅二医院儿童神经内科,长沙410011 [5]湖南师范大学附属长沙市妇幼保健院,长沙410007 [6]海口市妇幼保健院儿科,海口571000 [7]中南大学湘雅二医院儿童肾病科,长沙410011

出　　处：《中国医师杂志》2024年第12期1766-1772,共7页Journal of Chinese Physician

基　　金：海南省卫生健康科技创新联合项目(WSJK2024MS214);湖南省自然科学基金(2022JJ30064,2022JJ70048,2021SK53201);中央公益性研究机构基础研究(2022NHCTDCKFK T31004);海南省社发项目(ZDYF2021SHFZ088)。

摘　　要：目的研究内皮祖细胞(EPCs)对系统性红斑狼疮(SLE)动脉硬化小鼠的主动脉损伤的抑制作用。方法应用降植烷注射APOE^(-/-)小鼠和高脂饮食建立狼疮血管损伤模型,然后将实验小鼠分为正常对照组(ND组)、高脂饮食组(HFD组)、高脂饮食+SLE血管损伤组(HFD+SLE组)、高脂饮食+SLE血管损伤+羟氯喹治疗组(HFD+SLE+Hydro组)、高脂饮食+SLE血管损伤+EPCs治疗组(HFD+SLE+EPCs组),实验末采集各组小鼠的尿液、血液和主动脉组织,采用酶联免疫吸附法(ELISA)检测小鼠尿蛋白含量和血清Ⅰ型干扰素(IFN-Ⅰ)浓度,免疫组化和蛋白印迹法(WB)检测各组小鼠主动脉中环鸟苷酸腺苷酸合酶/干扰素基因刺激因子/Ⅰ型干扰素(cGAS/STING/IFN-1)通路的激活情况、炎症因子、黏附分子和趋化因子的水平,采用油红染色检测主动脉中脂质沉积情况。结果ELISA结果显示,与正常对照组比较,HFD+SLE组尿蛋白及血清IFN-Ⅰ水平升高,EPCs治疗可降低SLE动脉硬化小鼠尿蛋白和血清IFN-Ⅰ水平;WB结果显示,HFD+SLE组CD19、CD68、CD34、趋化因子以及cGAS、p-STING、磷酸化TANK结合激酶1(p-TBK1)、磷酸化干扰素调节因子3(p-IRF3)和IFN-Ⅰ表达升高,羟氯喹和EPCs能降低上述因子水平。cGAS/STING/IFN-Ⅰ信号通路参与了SLE动脉粥样硬化的发生发展;EPCs与羟氯喹均可抑制cGAS/STING/IFN-Ⅰ信号激活,从而减轻SLE小鼠的动脉硬化。结论cGAS/STING/IFN-Ⅰ通路参与了SLE动脉粥样硬化的发展。EPCs可通过抑制cGAS/STING信号活化,减少IFN-Ⅰ的表达与分泌,进而减轻血管炎症反应,阻抑SLE相关动脉粥样硬化的发展。ObjectiveTo study the inhibitory effect of endothelial progenitor cells(EPCs)on aortic injury in mice with systemic lupus erythematosus(SLE)arteriosclerosis.MethodsAPOE^(-/-)mice were injected with norphytane and high fat diet to establish lupus vascular injury model.Then the mice were divided into normal control group(ND group),high fat diet group(HFD group),high fat diet+SLE vascular injury group(HFD+SLE group),high fat diet+SLE vascular injury+hydroxychloroquine treatment group(HFD+SLE+Hydro group),high fat diet+SLE vascular injury+EPCs treatment group(HFD+SLE+EPCs group).At the end of the experiment,urine,blood and aortic tissues of mice in each group were collected,and the content of urinary protein and the depth of serum type I interferon(IFN-Ⅰ)were detected by enzyme linked immunosorbent assay(ELISA).The activation of cyclic guanosine monophosphate synthase/interferon gene stimulating factor/type I interferon(cGAS/STING/IFN-Ⅰ)pathway,the levels of inflammatory factors,adhesion fractions and chemokines in the aorta of mice in each group were detected by immunohistochemistry and Western blotting(WB).The lipid deposition in the aorta was detected by oil red staining.ResultsThe results of ELISA showed that the levels of urinary protein and serum IFN-Ⅰin HFD+SLE group were higher than those in normal control group.EPCs treatment could reduce the levels of urinary protein and serum IFN-Ⅰin SLE atherosclerotic mice.WB results showed that the expression of CD19,CD68,CD34,chemokine,cGAS,p-STING,phosphorylated TANK binding kinase 1(p-TBK1),phosphorylated interferon regulatory factor 3(p-IRF3)and IFN-Ⅰincreased in HFD+SLE group,and hydroxychloroquine and EPCs decreased the levels of these factors.CGAS/STING/IFN-Ⅰsignal pathway is involved in the occurrence and development of atherosclerosis in SLE patients;both EPCs and hydroxychloroquine can inhibit the activation of cGAS/STING/IFN-Ⅰsignal,thus reducing atherosclerosis in SLE mice.ConclusionscGAS/STING/IFN-Ⅰpathway is involved in the development of S

关 键 词：内皮祖细胞 红斑狼疮 系统性 动脉粥样硬化 Ⅰ型干扰素 cGAS/STING信号通路 

分 类 号：R593.241[医药卫生—内科学] R543.5[医药卫生—临床医学]