Therapeutic effects of artesunate on lupus-prone MRL/lpr mice are dependent on T follicular helper cell differentiation and activation of JAK2-STAT3 signaling pathway
Therapeutic effects of artesunate on lupus-prone MRL/lpr mice are dependent on T follicular helper cell differentiation and activation of JAK2-STAT3 signaling pathway
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青蒿琥酯对狼疮易感性 MRL/lpr 小鼠的治疗作用取决于滤泡辅助 T 细胞的分化和 JAK2-STAT3 信号通路的激活。
DOI：
10.1016/j.phymed.2019.152965
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发表时间：
2019-09-01
期刊：
影响因子：
7.9
通讯作者：
Zhou, Chun
中科院分区：
文献类型：
--
作者：
Dang, Wen-Zhen;Li, Hui;Zhou, Chun
背景：抗疟疾药物青蒿素（ART）是青蒿素的半合成衍生物，对多种自身免疫性疾病具有免疫抑制作用，包括系统性红斑狼疮（SLE）、类风湿性关节炎（RA）和结肠炎。然而，ART的分子机制，特别是对SLE病理学的核心参与者滤泡辅助性T细胞（Tfh）的分子机制尚不清楚。目的：本工作的目的是研究ART对狼疮易发性MRL/lpr小鼠的治疗效果及其对Tfh细胞的调节功能。研究设计和方法：以MRL/lpr小鼠为研究对象，探讨ART对狼疮易发性小鼠的治疗效果。 MRL/lpr 小鼠及其对 Tfh 细胞的调节功能。然后，使用生化试剂盒完成肾功能实验。使用 H&E 染色、ELISA 和实时 PCR 检查 ART 对肾脏组织病理学、炎症因子和自身抗体的影响。采用流式细胞术和蛋白质印迹分析检测ART对Tfh分化和Jak2-Stat3信号通路的影响。结果：口服ART后，ART显着延长MRL/lpr小鼠的生存期，改善狼疮性肾炎症状，降低肾脏中沉积的抗dsDNA抗体水平，以及致病细胞因子（IL-6、 IFN-γ 和 IL-21）。 ART 治疗后，MRL/lpr 小鼠脾脏中的 T 细胞区室得到恢复，Tfh 细胞数量减少，Tfr 与滤泡调节性 T 细胞 (Tfh) 比例维持不变。此外，ART还能显着抑制MRL/lpr小鼠中Jak2和Stat3的磷酸化水平。结论：ART通过抑制Tfh细胞的分化以及改变Jak2-Stat3信号级联的激活状态，对狼疮易发的MRL/lpr小鼠产生治疗作用。
Background: Anti-malarial drug artesunate (ART), a semi-synthetic derivative of artemisnin, has immunosuppressive effects on several autoimmune diseases, including Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), and Colitis. However, molecular mechanisms of ART, especially on follicular helper T cells (Tfh), central players in SLE pathology, are far from clear.Purpose: The object for this work is to investigate the therapeutic effect of ART on lupus-prone MRL/lpr mice and its regulatory function on Tfh cells.Study design and methods: MRL/lpr mice were used to explore therapeutic effects of ART on lupus-prone MRL/lpr mice and its regulatory functions on Tfh cells. Then, experiments of renal function were accomplished using the biochemical kits. Effects of ART on histopathology of kidneys, inflammatory factors and autoantibodies were examined using H&E staining, ELISA and real-time PCR. Flow cytometry and western blot analysis were used to examine effects of ART on Tfh differentiation and Jak2-Stat3 signaling pathway.Results: Upon oral administration, ART significantly prolonged the survival of MRL/lpr mice, ameliorated the lupus nephritis symptoms, decreased the levels of anti-dsDNA antibodies deposited in the kidney, and the levels of pathogenic cytokines (IL-6, IFN-gamma and IL-21). After ART treatment, T-cell compartment in the spleen of MRL/lpr mice was restored in terms of reduction in the number of Tfh cells and in the maintenance of the ratio of Tfr to follicular regulatory T cells (Tfh). In addition, ART has significantly inhibited the phosphorylation levels of Jak2 and Stat3 in the MRL/lpr mice.Conclusion: ART showed therapeutic effects on lupus-prone MRL/lpr mice by inhibiting the differentiation of Tfh cells as well as altering the activation status of Jak2-Stat3 signaling cascade.