MicroRNA-181b Regulates ALX/FPR2 Receptor Expression and Proresolution Signaling in Human Macrophages
MicroRNA-181b Regulates ALX/FPR2 Receptor Expression and Proresolution Signaling in Human Macrophages
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DOI：
10.1074/jbc.m114.592352
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发表时间：
2015-02-06
影响因子：
4.8
通讯作者：
Romano, Mario
中科院分区：
文献类型：
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作者：
Pierdomenico, Anna Maria;Recchiuti, Antonio;Romano, Mario
ALX/FPR2（脂氧素 A(4) 受体）表达的调节机制与炎症消退具有相当大的相关性。由于 microRNA (miR) 正在成为炎症消退的关键参与者，因此我们在此研究了 microRNA 介导的 ALX/FPR2（脂氧素 A4 受体/甲酰基肽受体 2）表达的调节。通过匹配生物信息算法的数据，我们发现 27 个 miR 预计会结合 ALX/FPR2 的 3'-UTR。其中，我们选择了 miR-181b，因为它与炎症有关。使用荧光素酶报告系统，我们评估了 miR-181b 与 ALX/FPR2 3'-UTR 的结合。与此一致的是，人巨噬细胞中的 miR-181b 过表达显着下调 ALX/FPR2 蛋白水平 (-25%)，而 miR-181b 敲低则使 ALX/FPR2 显着增加 (+60%)。在单核细胞向巨噬细胞分化过程中，miR-181b 水平下降 (-50%)，而 ALX/FPR2 表达显着增加 (+60%)。 miR-181b 过表达减弱了脂氧素 A(4) (0.1-10 nM) 和 resolvin D1 (0.01-10 nM) 刺激的巨噬细胞吞噬活性。这些结果揭示了 miR-181b 介导的 ALX/FPR2 表达和配体诱发巨噬细胞消退反应的新调节机制，从而揭示了内源性炎症消退回路的新成分。
Regulatory mechanisms of ALX/FPR2, the lipoxin A(4) receptor, expression have considerable relevance in inflammation resolution. Because microRNAs (miRs) are emerging as key players in inflammation resolution, here we examined microRNA-mediated regulation of ALX/FPR2 (lipoxin A4 receptor/formyl peptide receptor 2) expression. By matching data from bioinformatic algorithms, we found 27 miRs predicted to bind the 3'-UTR of ALX/FPR2. Among these, we selected miR-181b because of its link with inflammation. Using a luciferase reporter system, we assessed miR-181b binding to ALX/FPR2 3'-UTR. Consistent with this, miR-181b overexpression in human macrophages significantly down-regulated ALX/FPR2 protein levels (-25%), whereas miR-181b knockdown gave a significant increase in ALX/FPR2 (+60%). miR-181b levels decreased during monocyte to macrophage differentiation (-50%), whereas ALX/FPR2 expression increased significantly (+60%). miR-181b overexpression blunted lipoxin A(4) (0.1-10 nM)-and resolvin D1 (0.01-10 nM)-stimulated phagocytic activity of macrophages. These results unravel novel regulatory mechanisms of ALX/FPR2 expression and ligand-evoked macrophages proresolution responses mediated by miR-181b, thus uncovering novel components of the endogenous inflammation resolution circuits.