MicroRNA-33–dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis Academic Article uri icon

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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

  • Ouimet, Mireille
  • Ediriweera, Hasini N
  • Gundra, U Mahesh
  • Sheedy, Frederick J
  • Ramkhelawon, Bhama
  • Hutchison, Susan B
  • Rinehold, Kaitlyn
  • van Solingen, Coen
  • Fullerton, Morgan D
  • Cecchini, Katharine
  • Rayner, Katey J
  • Steinberg, Gregory
  • Zamore, Phillip D
  • Fisher, Edward A
  • Loke, P ng
  • Moore, Kathryn J

publication date

  • October 26, 2015