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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^sup +^ T cells. Finally, treatment of hypercholesterolemic mice with miR-33 inhibitors for 8 weeks resulted in accumulation of inflammation-suppressing M2 macrophages and FOXP3^sup +^ 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.
Introduction
Macrophages are critical effectors of inflammation and innate immunity; they also regulate adaptive immunity by recruiting and/or activating other immune cells at inflammatory foci (1). In addition, macrophages play important roles in tissue homeostasis and resolution of inflammation (2). To fulfill these functions, macrophages can adopt a spectrum of activation programs depending on the context. M1, or classical activation, represents one end in response to products from bacterial infection such as LPS and IFN-γ, whereas M2, or alternative activation, occurs in response to the cytokines IL-4 and IL-13 (2). Although originally defined in the context of host defense against parasitic helminths (3), M2 macrophages are now appreciated as being important orchestrators of inflammation resolution and metabolic homeostasis through their secretion of antiinflammatory cytokines (e.g., IL-10 and TGF-β), mediators of tissue repair (eg. collagen), and catecholamines (4). Moreover, monocyte-derived M2 macrophages were recently shown to be an important source of retinoic acid (5), a hormonelike metabolite that promotes the...