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

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 PPAR gamma/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, PPAR gamma directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays; revealed that this effect was mediated by PPAR gamma binding 3 PPAR gamma regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPAR gamma-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified Pascal and Nfat5 as genuine miR-223 targets that are critical for PPAR gamma-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 PPAR gamma/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.