ApoE and miR-146 in inflammation and atherosclerosis

Apolipoprotein E (ApoE) enhances purine-rich PU-box-binding protein 1 (PU.1)-dependent miR-146a transcription to suppress nuclear factor-κB (NF-κB)-driven monocyte and macrophage activation and thereby inflammation and atherosclerosis. Environmental ligands of toll-like receptors (TLRs), including lipopolysaccharide (LPS) and oxidized low-density lipoprotein (oxLDL), caused by hyperlipidemia provoke inflammatory signaling in monocytes and macrophages resulting in NF-κB activation. Gene transcription from NF-κB activity results in the production of inflammatory mediators, including proatherogenic cytokines. It also results in the production of primary miR-146a (pri-miR-146a) that is subsequently processed into mature miR-146a that silences the expression of key TLR-adaptor molecules interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6). The production of miR-146a thereby serves as a regulatory feedback loop to suppress NF-κB activity and resolve inflammation. Findings from our study identified that cellular apoE expression contributes to amplify this regulatory feedback loop by increasing PU.1-dependent transcription of pri-miR-146a and thereby mature miR-146a production.

载脂蛋白E（ApoE）通过增强富含嘌呤的PU-box结合蛋白1（PU.1）依赖性miR-146a转录，进而抑制核因子-κB（NF-κB）驱动的单核细胞和巨噬细胞活化，从而抑制炎症和动脉粥样硬化。由高脂血症引起的TLR（Toll样受体）环境配体，包括脂多糖（LPS）和氧化低密度脂蛋白（oxLDL），可诱导单核细胞和巨噬细胞的炎症信号传导，导致NF-κB激活。NF-κB活性的基因转录导致炎症介质的产生，包括促动脉粥样硬化性细胞因子。此外，它还导致初级miR-146a（pri-miR-146a）的产生，随后经过加工成为成熟的miR-146a，该miR-146a能够沉默关键TLR适配分子白细胞介素-1受体相关激酶1（IRAK1）和TNF受体相关因子6（TRAF6）的表达。miR-146a的产生因此作为一种调控反馈回路，以抑制NF-κB活性和缓解炎症。我们研究的结果表明，细胞内ApoE的表达通过增加PU.1依赖性的pri-miR-146a转录，从而促进成熟miR-146a的产生，进而放大这一调控反馈回路。