title: MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis.
abstract: Cellular metabolism is increasingly recognized as a controller of immune cell fate and function. MicroRNA-33 (miR-33) regulates cellular lipid metabolism and represses genes involved in cholesterol efflux, HDL biogenesis, and fatty acid oxidation. Here, we determined that miR-33-mediated disruption of the balance of aerobic glycolysis and mitochondrial oxidative phosphorylation instructs macrophage inflammatory polarization and shapes innate and adaptive immune responses. Macrophage-specific Mir33 deletion increased oxidative respiration, enhanced spare respiratory capacity, and induced an M2 macrophage polarization-associated gene profile. Furthermore, miR-33-mediated M2 polarization required miR-33 targeting of the energy sensor AMP-activated protein kinase (AMPK), but not cholesterol efflux. Notably, miR-33 inhibition increased macrophage expression of the retinoic acid-producing enzyme aldehyde dehydrogenase family 1, subfamily A2 (ALDH1A2) and retinal dehydrogenase activity both in vitro and in a mouse model. Consistent with the ability of retinoic acid to foster inducible Tregs, miR-33-depleted macrophages had an enhanced capacity to induce forkhead box P3 (FOXP3) expression in naive CD4(+) T cells. Finally, treatment of hypercholesterolemic mice with miR-33 inhibitors for 8 weeks resulted in accumulation of inflammation-suppressing M2 macrophages and FOXP3(+) Tregs in plaques and reduced atherosclerosis progression. Collectively, these results reveal that miR-33 regulates macrophage inflammation and demonstrate that miR-33 antagonism is atheroprotective, in part, by reducing plaque inflammation by promoting M2 macrophage polarization and Treg induction.
authors.forename: Mireille
authors.initials: M
authors.lastname: Ouimet
authors.forename: Hasini N
authors.initials: HN
authors.lastname: Ediriweera
authors.forename: U Mahesh
authors.initials: UM
authors.lastname: Gundra
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Sheedy
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.forename: Susan B
authors.initials: SB
authors.lastname: Hutchison
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Rinehold
authors.forename: Coen
authors.initials: C
authors.lastname: van Solingen
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Fullerton
authors.forename: Katharine
authors.initials: K
authors.lastname: Cecchini
authors.forename: Katey J
authors.initials: KJ
authors.lastname: Rayner
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Zamore
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: P'ng
authors.initials: P
authors.lastname: Loke
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000276:immunology; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D006019:Glycolysis / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D010101:Oxygen Consumption / Q000235:genetics / Q000276:immunology; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050697:Retinal Dehydrogenase; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase; D055372:AMP-Activated Protein Kinases