Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway.
Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway.
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DOI：
10.1007/s00018-022-04331-0
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发表时间：
2022-05-22
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巨噬细胞的炎症反应在动脉粥样硬化中起着重要作用。巨噬细胞的炎症状态通过表观遗传重编程来改变。m6 A RNA甲基化是RNA的表观遗传修饰。然而，关于m6 A修饰在巨噬细胞炎症中的潜在作用和潜在机制知之甚少。在此，我们表明，在冠心病和LPS刺激的THP-1细胞中，m6 A修饰“作家”Mettl 14的表达增加。Mettl 14的敲低促进了巨噬细胞的M2极化，抑制了泡沫细胞的形成并减少了迁移。在机制上，Myd 88和IL-6的表达在Mettl 14敲减细胞中降低。Mettl 14通过m6 A修饰调控Myd 88 mRNA的稳定性。此外，Myd 88通过p65在细胞核中的分布影响IL-6的转录，而不是通过m6 A修饰直接调节IL-6的表达。在体内，Mettl 14基因敲除显著降低巨噬细胞的炎症反应和动脉粥样硬化斑块的发展。综上所述，我们的数据表明，Mettl 14通过NF-κB/IL-6信号通路在动脉粥样硬化的巨噬细胞炎症中起着至关重要的作用，这表明Mettl 14可能是临床治疗动脉粥样硬化的有希望的治疗靶点。在线版本包含补充材料，可通过10.1007/s 00018 -022-04331-0获得。
The inflammatory response of macrophages has been reported to play a critical role in atherosclerosis. The inflammatory state of macrophages is modified by epigenetic reprogramming. m6A RNA methylation is an epigenetic modification of RNAs. However, little is known about the potential roles and underlying mechanisms of m6A modification in macrophage inflammation. Herein, we showed that the expression of the m6A modification “writer” Mettl14 was increased in coronary heart disease and LPS-stimulated THP-1 cells. Knockdown of Mettl14 promoted M2 polarization of macrophages, inhibited foam cell formation and decreased migration. Mechanistically, the expression of Myd88 and IL-6 was decreased in Mettl14 knockdown cells. Through m6A modification, Mettl14 regulated the stability of Myd88 mRNA. Furthermore, Myd88 affected the transcription of IL-6 via the distribution of p65 in nuclei rather than directly regulating the expression of IL-6 through m6A modification. In vivo, Mettl14 gene knockout significantly reduced the inflammatory response of macrophages and the development of atherosclerotic plaques. Taken together, our data demonstrate that Mettl14 plays a vital role in macrophage inflammation in atherosclerosis via the NF-κB/IL-6 signaling pathway, suggesting that Mettl14 may be a promising therapeutic target for the clinical treatment of atherosclerosis. The online version contains supplementary material available at 10.1007/s00018-022-04331-0.
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影响因子：
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作者：
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DOI：
10.12703/p6-97
发表时间：
2014
期刊：
F1000prime reports
影响因子：
--
作者：
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通讯作者：
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