Objectives

The objective of this study was to address the biological function of miR-7 in an animal model of systemic lupus erythematosus.

Methods

MRL^lpr/lpr lupus mice were administrated antagomiR-7 or a scramble control by tail vein for 5weeks. Three groups of animals’ tissues were assessed for lupus manifestations by immunofluorescence and immunohistochemistry, and serum was examined for levels of autoantibodies and inflammatory cytokines. Splenic B cell subsets were assessed for intracellular expression of PI3K signaling by FACS. Finally, the ability of the miR-7 antagomir to regulate the expansion of T follicular helper (Tfh) cells and B cell hyperresponsiveness was further explored.

Results

We found that miR-7 was up-regulated in MRL^lpr/lpr lupus mice and directly targeted PTEN mRNA in B cells. Up-regulated miR-7 in MRL^lpr/lpr lupus B cells was negatively correlated with PTEN expression. Notably, miR-7 antagomir treatment reduced lupus manifestations in MRL^lpr/lpr lupus mice. miR-7-mediated down-regulation of PTEN/AKT signaling promoted B cell differentiation into plasmablasts/plasma cells and spontaneous germinal center (GC) formation, whereas miR-7 antagomir normalized splenic B cell subtypes. Besides suppressing the activation of B cells, miR-7 antagomir intervention also down-regulated STAT3 phosphorylation and production of IL-21 and reduced Tfh expansion.

Conclusion

The above data have demonstrated the critical roles of miR-7 not only in regulating PTEN expression and also B cell and Tfh cell function in lupus-prone MRL^lpr/lpr lupus mice. Furthermore, the disease manifestations in MRL^lpr/lpr lupus mice are efficiently improved by miR-7 antagomir, indicating miR-7 as a potential treatment strategy in SLE.

中文翻译：

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拮抗 miR-7 抑制 B 细胞高反应性并抑制狼疮发展

目标

本研究的目的是探讨 miR-7 在系统性红斑狼疮动物模型中的生物学功能。

方法

MRL ^lpr/lpr狼疮小鼠通过尾静脉给予antagomiR-7或争夺对照5周。通过免疫荧光和免疫组织化学评估三组动物组织的狼疮表现，并检查血清中的自身抗体和炎性细胞因子的水平。通过 FACS 评估脾 B 细胞亚群的 PI3K 信号的细胞内表达。最后，进一步探索了 miR-7 antagomir 调节 T 滤泡辅助 (Tfh) 细胞扩增和 B 细胞高反应性的能力。

结果

我们发现 miR-7 在 MRL ^lpr/lpr狼疮小鼠中上调并直接靶向 B 细胞中的 PTEN mRNA。MRL ^lpr/lpr狼疮B细胞中上调的miR-7与PTEN表达呈负相关。值得注意的是，miR-7 antagomir 治疗减少了 MRL ^lpr/lpr狼疮小鼠的狼疮表现。miR-7 介导的 PTEN/AKT 信号下调促进 B 细胞分化为浆母细胞/浆细胞和自发生发中心 (GC) 形成，而 miR-7 antagomir 使脾 B 细胞亚型正常化。除了抑制 B 细胞的活化外，miR-7 antagomir 干预还下调 STAT3 磷酸化和 IL-21 的产生并减少 Tfh 扩增。

结论

上述数据证明了 miR-7 不仅在调节 PTEN 表达以及 B 细胞和 Tfh 细胞功能中的关键作用，在易患狼疮的 MRL ^lpr/lpr狼疮小鼠中。此外，miR-7 antagomir 可有效改善MRL ^lpr/lpr狼疮小鼠的疾病表现，表明 miR-7 可作为 SLE 的潜在治疗策略。