ADAR1 attenuates allogeneic graft rejection by suppressing miR-21 biogenesis in macrophages and promoting M2 polarization
ADAR1 attenuates allogeneic graft rejection by suppressing miR-21 biogenesis in macrophages and promoting M2 polarization
复制标题
ADAR1 通过抑制巨噬细胞中的 miR-21 生物合成和促进 M2 极化来减轻同种异体移植物排斥
DOI：
10.1096/fj.201701449r
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发表时间：
2018-09-01
期刊：
影响因子：
4.8
通讯作者：
Yin, Wen
中科院分区：
文献类型：
--
作者：
Li, Junjie;Xie, Jiangang;Yin, Wen
ADAR 1（adenosine deaminase acting on double-stranded RNA 1）是一种RNA编辑酶，介导腺苷到肌苷的RNA编辑事件，这是一种重要的转录后修饰机制，可以改变mRNA的编码特性或调节microRNA的生物合成。ADAR 1还调节先天免疫反应。在这里，我们已经证明，ADAR 1的表达增加LPS刺激的巨噬细胞。在巨噬细胞中使用小干扰RNA沉默ADAR 1导致巨噬细胞明显向M1极化，而ADAR 1过表达促进M2极化，这表明ADAR 1可以抑制巨噬细胞超极化并防止免疫亢进。RNA-RNP免疫沉淀结合试验证实了ADAR 1与miR-21前体之间的直接相互作用。在ADAR 1过表达的巨噬细胞中观察到IL-10的显著上调和miR-21的显著下调。我们评估了miR-21靶mRNA和巨噬细胞极化信号通路，发现叉头盒蛋白O 1（Foxo 1）在过表达ADAR 1的细胞中上调。在小鼠同种异体皮肤移植模型中，ADAR 1过表达组的移植物存活时间更长，免疫细胞浸润更少。在ADAR 1过表达的受者中，脾巨噬细胞明显极化为M2，血清IL-10水平明显高于对照组。总之，ADAR 1通过ADAR 1-miR-21-Foxo 1-IL-10轴调节巨噬细胞M2极化，从而抑制同种异体移植排斥。谢，J.，Liu，S.，Li，X.，Zhang，D.，中国农业科学院农业研究所所长，王，X.，姜杰，胡伟，张玉，Jin，B.，Zhuang，R.，殷，W. ADAR 1通过抑制巨噬细胞中的miR-21生物合成和促进M2极化来减弱同种异体移植物排斥。
ADAR1 (adenosine deaminase acting on double-stranded RNA 1) is an RNA-editing enzyme that mediates adenosine-to-inosine RNA editing events, an important post-transcriptional modification mechanism that can alter the coding properties of mRNA or regulate microRNA biogenesis. ADAR1 also regulates the innate immune response. Here, we have demonstrated that ADAR1 expression increased in LPS-stimulated macrophages. Silencing ADAR1 by using small interfering RNA in macrophages resulted in the pronounced polarization of macrophages to M1, whereas ADAR1 overexpression promoted M2 polarization, which indicated that ADAR1 can inhibit macrophage hyperpolarization and prevent immune hyperactivity. The RNA-RNP immunoprecipitation binding assay demonstrated a direct interaction between ADAR1 and miR-21 precursor. Significant up-regulation in IL-10 and down-regulation in miR-21 were observed in ADAR1-overexpressing macrophages. We evaluated miR-21 target mRNAs and macrophage polarization signaling pathways and found that forkhead box protein O1 (Foxo1) was up-regulated in cells that overexpressed ADAR1. In a mouse allogeneic skin transplantation model, grafts in the ADAR1-overexpressed group survived longer and suffered less immune cell infiltration. In ADAR1-overexpressed recipients, splenic macrophages were significantly polarized to M2, and levels of sera IL-10 were markedly higher than those in the control group. In summary, ADAR1 modulates macrophage M2 polarization via the ADAR1-miR-21-Foxo1-IL-10 axis, thereby suppressing allogeneic graft rejection.Li, J., Xie, J., Liu, S., Li, X., Zhang, D., Wang, X., Jiang, J., Hu, W., Zhang, Y., Jin, B., Zhuang, R., Yin, W. ADAR1 attenuates allogeneic graft rejection by suppressing miR-21 biogenesis in macrophages and promoting M2 polarization.