Abstract 155: MicroRNA-146a Suppression of NF-κB-driven Monocyte/Macrophage Activation and Atherosclerosis is Regulated by Cellular ApoE Expression

Abstract

Apolipoprotein E (apoE) exerts anti-inflammatory properties that protect against atherosclerosis and other inflammatory diseases. However, the mechanisms by which apoE suppresses the activation of leukocytes remain incompletely understood. An assessment of apoE expression levels among major leukocyte subsets in wild-type mice revealed that only macrophages and monocytes express apoE abundantly. An absence of Apoe expression in mouse macrophages and monocytes resulted in enhanced NF-κB signaling and an exaggerated inflammatory response upon stimulation with lipopolysaccharide. This correlated with reduced levels of microRNA-146a, a critical negative regulator of NF-κB signaling. Restoration of apoE expression in Apoe-/- macrophages and monocytes enhanced miR-146a levels, while silencing apoE expression in wild-type mouse monocytes reduced miR-146a levels. Mechanistically, apoE increased the expression of transcription factor PU.1, which raised levels of pri-miR-146 transcripts, demonstrating that apoE exerts a 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, which inhibited macrophage proinflammatory responses, Ly-6Chigh monocytosis and atherosclerosis in the settings of hyperlipidemia. Accordingly, cellular enrichment of miR-146a through the systemic delivery of miR-146a mimics emulsified in lipid microparticles infused into apoE deficient mice attenuated systemic inflammation and atherosclerosis in the absence of plasma lipid reduction. Together, our data demonstrate that apoE suppresses NF-κB-mediated inflammation and atherosclerosis by enhancing miR-146a levels in monocytes and macrophages. Ongoing studies are exploring the impact of apoE on the cellular release of endogenous miR-146a in exosomes and high density lipoproteins from macrophages that can be communicated to cells in the circulation and artery to suppress inflammation and atherosclerosis.