Apolipoprotein E Enhances MicroRNA-146a in Monocytes and Macrophages to Suppress Nuclear Factor-kappa B-Driven Inflammation and Atherosclerosis

作者：Li Kang; Ching Daniel; Luk Fu Sang; Raffai Robert L^*

来源：Circulation Research, 2015, 117(1): e1-e11.

DOI：10.1161/CIRCRESAHA.117.305844

• atherosclerosis
• apolipoproteins E
• macrophages
• microRNAs

Rationale: Apolipoprotein E (apoE) exerts anti-inflammatory properties that protect against atherosclerosis and other inflammatory diseases. However, mechanisms by which apoE suppresses the cellular activation of leukocytes commonly associated with atherosclerosis remain incompletely understood.
Objective: To test the hypothesis that apoE suppresses inflammation and atherosclerosis by regulating cellular microRNA levels in these leukocytes.
Methods and Results: An assessment of apoE expression among such leukocyte subsets in wild-type mice revealed that only macrophages and monocytes express apoE abundantly. An absence of apoE expression in macrophages and monocytes resulted in enhanced nuclear factor-B signaling and an exaggerated inflammatory response on stimulation with lipopolysaccharide. This correlated with reduced levels of microRNA-146a, a critical negative regulator of nuclear factor-B signaling. Ectopic apoE expression in Apoe(-/-) macrophages and monocytes raised miR-146a levels, whereas its silencing in wild-type cells had an opposite effect. Mechanistically, apoE increased the expression of transcription factor purine-rich PU-box-binding protein 1, which raised levels of pri-miR-146 transcripts, demonstrating that apoE exerts transcriptional control over miR-146a. In vivo, even a small amount of apoE expression in macrophages and monocytes of hypomorphic apoE mice led to increased miR-146a levels, and inhibited macrophage proinflammatory responses, Ly-6C(high) monocytosis, and atherosclerosis in the settings of hyperlipidemia. Accordingly, cellular enrichment of miR-146a through the systemic delivery of miR-146a mimetics in Apoe(-/-)Ldlr(-/-) and Ldlr(-/-) mice attenuated monocyte/macrophage activation and atherosclerosis in the absence of plasma lipid reduction.
Conclusions: Our data demonstrate that cellular apoE expression suppresses nuclear factor-B-mediated inflammation and atherosclerosis by enhancing miR-146a levels in monocytes and macrophages.

• 出版日期2015-6-19