MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis.

نویسندگان

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

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.

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عنوان ژورنال:
  • The Journal of clinical investigation

دوره 125 12  شماره 

صفحات  -

تاریخ انتشار 2015