| First Author | Ying W | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 11 | Pages | 4149-59 |
| PubMed ID | 26436647 | Mgi Jnum | J:227488 |
| Mgi Id | MGI:5700587 | Doi | 10.1172/JCI81656 |
| Citation | Ying W, et al. (2015) MicroRNA-223 is a crucial mediator of PPARgamma-regulated alternative macrophage activation. J Clin Invest 125(11):4149-59 |
| abstractText | 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 PPARgamma/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, PPARgamma directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARgamma binding 3 PPARgamma regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPARgamma-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 PPARgamma-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 PPARgamma/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes. |
