Self-limited versus delayed resolution of acute inflammation: temporal regulation of pro-resolving mediators and microRNA.
Self-limited versus delayed resolution of acute inflammation: temporal regulation of pro-resolving mediators and microRNA.
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DOI：
10.1038/srep00639
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发表时间：
2012
影响因子：
4.6
通讯作者：
Serhan, Charles N.
中科院分区：
文献类型：
--
作者：
Fredman, Gabrielle;Li, Yongsheng;Dalli, Jesmond;Chiang, Nan;Serhan, Charles N.
炎症消退程序延迟的潜在机制是许多疾病的关注点。在这里，我们解决了炎症的延迟消退，并确定了特定的microRNA（miR）-代谢脂质组学特征。由高剂量激发引发的延迟消退降低了miR-219- 5 p表达沿着增加了白三烯B4（5倍）和降低了（约3倍）专门的促消退介质，例如保护素D1。Resolvin（Rv）E1和RvD 1（1 nM）可减少人巨噬细胞中的miR-219- 5 p，而RvD 2或PD 1则不共享。 由于成熟的miR-219- 5 p是由前miR-219-1和miR-219-2产生的，我们在人巨噬细胞中共表达了5-脂氧合酶（LOX）3′ UTR-荧光素酶报告载体以及miR-219-1或miR-219-2。只有miR-219-2降低荧光素酶活性。向体内发炎渗出液中给予凋亡中性粒细胞可增加miR-219-2- 3 p表达和PD 1/NPD 1水平，并降低白三烯B4。这些结果表明，延迟消退破坏了内源性消退程序，改变了miR-219-2表达，增加了促炎介质并损害了SPM产生，导致缓解和稳态失败。
Mechanisms underlying delays in resolution programs of inflammation are of interest for many diseases. Here, we addressed delayed resolution of inflammation and identified specific microRNA (miR)-metabolipidomic signatures. Delayed resolution initiated by high-dose challenges decreased miR-219-5p expression along with increased leukotriene B4 (5-fold) and decreased (~3-fold) specialized pro-resolving mediators, e.g. protectin D1. Resolvin (Rv)E1 and RvD1 (1 nM) reduced miR-219-5p in human macrophages, not shared by RvD2 or PD1. Since mature miR-219-5p is produced from pre-miRs miR-219-1 and miR-219-2, we co-expressed in human macrophages a 5-lipoxygenase (LOX) 3′UTR-luciferase reporter vector together with either miR-219-1 or miR-219-2. Only miR-219-2 reduced luciferase activity. Apoptotic neutrophils administered into inflamed exudates in vivo increased miR-219-2-3p expression and PD1/NPD1 levels as well as decreased leukotriene B4. These results demonstrate that delayed resolution undermines endogenous resolution programs, altering miR-219-2 expression, increasing pro-inflammatory mediators and compromising SPM production that contribute to failed catabasis and homeostasis.
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