title: Apolipoprotein E enhances microRNA-146a in monocytes and macrophages to suppress nuclear factor-κB-driven inflammation and atherosclerosis.
abstract: BACKGROUND
  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.
  
  
  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-κB 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-κB 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-κB-mediated inflammation and atherosclerosis by enhancing miR-146a levels in monocytes and macrophages.
authors.affiliation: From the Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco and Veterans Affairs Medical Center.
authors.forename: Kang
authors.initials: K
authors.lastname: Li
authors.affiliation: From the Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco and Veterans Affairs Medical Center.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ching
authors.affiliation: From the Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco and Veterans Affairs Medical Center.
authors.forename: Fu Sang
authors.initials: FS
authors.lastname: Luk
authors.affiliation: From the Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco and Veterans Affairs Medical Center. robert.raffai@ucsf.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Raffai
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D059305:Diet, High-Fat / Q000009:adverse effects; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011973:Receptors, LDL / Q000172:deficiency; D013047:Specific Pathogen-Free Organisms; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D001057:Apolipoproteins E; D008070:Lipopolysaccharides; D035683:MicroRNAs; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C534190:Mirn146 microRNA, mouse
keywords: apolipoproteins E; atherosclerosis; macrophages; microRNAs