Targeting of EIF4EBP1 by miR-99a-3p affects the functions of B lymphocytes via autophagy and aggravates SLE disease progression.
Targeting of EIF4EBP1 by miR-99a-3p affects the functions of B lymphocytes via autophagy and aggravates SLE disease progression.
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miR-99a-3p靶向EIF4EBP1通过自噬影响B淋巴细胞的功能并加剧SLE疾病进展
DOI：
10.1111/jcmm.16991
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发表时间：
2021-11
影响因子：
5.3
通讯作者：
Deng D
中科院分区：
文献类型：
--
作者：
Yang M;Yang B;Deng D
免疫细胞的过度激活在系统性红斑狼疮（SLE）的发病机制中起着关键作用。miRNAs对免疫细胞的调控是目前的研究热点。在这项研究中，第二代高通量测序显示SLE患者的miR-99 a-3 p表达减少;然而，这种现象背后的具体机制仍不清楚。转染miR-99 a-3 p agomir后，Ball-1细胞的增殖降低，凋亡水平增加。在用miR-99 a-3 p转染的细胞中观察到相反的效果。荧光素酶报告基因分析表明miR-99 a-3 p直接靶向EIF 4 EBP 1。拯救实验证实了miR-99 a-3 p和EIF 4 EBP 1之间的相互作用。体外、体内和临床研究进一步证实，miR-99 a-3 p agomir可降低EIF 4 EBP 1、LC 3B和LAMP-2A的表达。在体内实验中，西洛莫组小鼠的抗核抗体、双链DNA、IgE、IgM、IL-6、IL-10和B淋巴细胞刺激因子的血清水平高于MRL/lpr组小鼠。此外，EIF 4 EBP 1、LC 3B和LAMP-2A的蛋白质和mRNA水平、EIF 4 EBP 1、LC 3B和LAMP-2A的免疫组织化学染色强度、尿蛋白水平和C3免疫荧光沉积在EIF 4 EBP 1、LC 3B和LAMP-2A组小鼠中增加。miR-99 a-3 p表达上调可保护B细胞免受EIF 4 EBP 1介导的自噬，而miR-99 a-3 p表达下调可通过EIF 4 EBP 1介导的自噬信号通路调节从SLE个体分离的B细胞中诱导自噬。基于这些结果，miR-99 a-3 p和EIF 4 EBP 1可能被认为是SLE治疗的潜在靶点。
Excessive activation of immune cells plays a key role in the pathogenesis of systemic lupus erythematosus (SLE). The regulation of immune cells by miRNAs is a research hotspot. In this study, second‐generation high‐throughput sequencing revealed a reduction in miR‐99a‐3p expression in patients with SLE; however, the specific mechanism underlying this phenomenon remains unclear. After transfection with an miR‐99a‐3p agomir, the proliferation of Ball‐1 cells decreased and the levels of their apoptosis increased. The opposite effects were observed in cells transfected with the miR‐99a‐3p antagomir. Luciferase reporter assay indicated that miR‐99a‐3p directly targeted EIF4EBP1. Rescue experiments confirmed the proposed interaction between miR‐99a‐3p and EIF4EBP1. In vitro, in vivo and clinical investigations further confirmed that the miR‐99a‐3p agomir reduced the expression of EIF4EBP1, LC3B and LAMP‐2A. In the in vivo experiments, serum levels of anti‐nuclear antibodies, double‐stranded DNA, IgE, IgM, IL‐6, IL‐10 and B lymphocyte stimulator were higher in mice from the antagomir group than those in mice from the MRL/lpr group. Furthermore, the protein and mRNA levels of EIF4EBP1, LC3B and LAMP‐2A, the intensity of immunohistochemical staining of EIF4EBP1, LC3B and LAMP‐2A, the urinary protein levels, and the C3 immunofluorescence deposition increased in mice from the antagomir group. The upregulation of miR‐99a‐3p expression protected B cells from EIF4EBP1‐mediated autophagy, whilst the downregulation of miR‐99a‐3p expression induced autophagy via the EIF4EBP1‐mediated regulation of the autophagy signalling pathway in B cells isolated from individuals with SLE. Based on these results, miR‐99a‐3p and EIF4EBP1 may be considered potential targets for SLE treatment.
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