MicroRNA-223 is a crucial mediator of PPARγ-regulated alternative macrophage activation

J Clin Invest. 2015 Nov 2;125(11):4149-59. doi: 10.1172/JCI81656. Epub 2015 Oct 5.


Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARγ/microRNA-223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARγ directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARγ binding 3 PPARγ regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPARγ-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified Rasa1 and Nfat5 as genuine miR-223 targets that are critical for PPARγ-dependent macrophage alternative activation, whereas the proinflammatory regulator Pknox1, which we reported previously, mediated miR-223-regulated macrophage classical activation. In summary, this study provides evidence to support the crucial role of a PPARγ/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adipocytes / pathology
  • Animals
  • Bone Marrow / pathology
  • Chromatin Immunoprecipitation
  • Diet, High-Fat / adverse effects
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation / immunology
  • Genes, Reporter
  • Homeodomain Proteins / physiology
  • Inflammation / immunology
  • Inflammation / pathology
  • Insulin Resistance
  • Intra-Abdominal Fat / immunology*
  • Intra-Abdominal Fat / pathology
  • Macrophage Activation / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • PPAR gamma / physiology*
  • Pioglitazone
  • Protein Binding
  • Stromal Cells / pathology
  • Th2 Cells / immunology
  • Thiazolidinediones / pharmacology
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • p120 GTPase Activating Protein / biosynthesis
  • p120 GTPase Activating Protein / genetics


  • 3' Untranslated Regions
  • Homeodomain Proteins
  • MIRN223 microRNA, mouse
  • MicroRNAs
  • Nfat5 protein, mouse
  • PPAR gamma
  • Pknox1 protein, mouse
  • RASA1 protein, mouse
  • Thiazolidinediones
  • Transcription Factors
  • p120 GTPase Activating Protein
  • Pioglitazone