Dynamic macrophage polarization-specific miRNA patterns reveal increased soluble VEGF receptor 1 by miR-125a-5p inhibition
Dynamic macrophage polarization-specific miRNA patterns reveal increased soluble VEGF receptor 1 by miR-125a-5p inhibition
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DOI：
10.1152/physiolgenomics.00098.2015
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发表时间：
2016-05-01
影响因子：
4.6
通讯作者：
Shireman, Paula K.
中科院分区：
文献类型：
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作者：
Melton, David W.;Lei, XiuFen;Shireman, Paula K.
动态的表观遗传机制可以调节巨噬细胞暴露于不同刺激条件和环境后的表型。然而，microrna （mirna或miRs）在多种巨噬细胞极化表型中的时间模式尚未确定。我们在暴露于细胞因子和/或LPS后的多个时间点（0.5、1、3、24小时）检测了骨髓源性小鼠巨噬细胞中miRNA的表达。我们假设mirna的动态变化调节巨噬细胞表型。早在0.5 h和晚在24 h检测到巨噬细胞极化标志物的变化；然而，大多数标记在3小时内发生了强烈的反应。与此同时，许多极化特异性mirna也在3小时内发生了变化，并且在M1和M2a条件下表达不同的模式，M1 （miR-155, 199a-3p, 214-3p， 455-3p和125a）或M2a （miR-511和449a）中的表达增加。具体来说，miR-125a-5p表现出不同的模式：在M1巨噬细胞中12-24 h升高，在M2a中呈下降趋势。巨噬细胞培养基中的VEGF依赖于极化状态，尽管细胞裂解物中VEGF相似，但与M1巨噬细胞培养基相比，M2a中VEGF明显降低。在培养基纯对照（MO）和M1巨噬细胞中抑制miR-125a-5p大大增加可溶性VEGF受体-1 （sVEGFR1）的表达和分泌，导致培养基中VEGF减少，部分将MO和M1转化为M2a表型。因此，极化特异性mirna的不同表达模式导致鉴定并证明了通过抑制miR-125a-5p对巨噬细胞特异性极化表型sVEGFR1的调节。
Dynamic, epigenetic mechanisms can regulate macrophage phenotypes following exposure to different stimulating conditions and environments. However, temporal patterns of microRNAs (miRNAs or miRs) across multiple macrophage polarization phenotypes have not been defined. We determined miRNA expression in bone marrow-derived murine macrophages over multiple time points (0.5, 1, 3, 24 h) following exposure to cytokines and/or LPS. We hypothesized that dynamic changes in miRNAs regulate macrophage phenotypes. Changes in macrophage polarization markers were detected as early as 0.5 and as late as 24 h; however, robust responses for most markers occurred within 3 h. In parallel, many polarization-specific miRNAs were also changed by 3 h and expressed divergent patterns between M1 and M2a conditions, with increased expression in M1 (miR-155, 199a-3p, 214-3p, 455-3p, and 125a) or M2a (miR-511 and 449a). Specifically, miR-125a-5p exhibited divergent patterns: increased at 12-24 h in M1 macrophages and decreasing trend in M2a. VEGF in the culture media of macrophages was dependent upon the polarization state, with greatly diminished VEGF in M2a compared with M1 macrophage culture media despite similar VEGF in cell lysates. Inhibition of miR-125a-5p in media-only controls (MO) and M1 macrophages greatly increased expression and secretion of soluble VEGF receptor-1 (sVEGFR1) leading to diminished VEGF in the culture media, partially converting MO and M1 into an M2a phenotype. Thus, the divergent expression patterns of polarization-specific miRNAs led to the identification and demonstrated the regulation of a specific macrophage polarization phenotype, sVEGFR1 by inhibition of miR-125a-5p.