MicroRNA-223 is a crucial mediator of PPAR-regulated alternative macrophage activation.
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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/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 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 binding 3 PPAR regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPAR-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 PPAR-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/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.
author list (cited authors)
Ying, W., Tseng, A., Chang, R., Morin, A., Brehm, T., Triff, K., ... Zhou, B.
complete list of authors
Ying, Wei||Tseng, Alexander||Chang, Richard Cheng-An||Morin, Andrew||Brehm, Tyler||Triff, Karen||Nair, Vijayalekshmi||Zhuang, Guoqing||Song, Hui||Kanameni, Srikanth||Wang, Haiqing||Golding, Michael C||Bazer, Fuller W||Chapkin, Robert S||Safe, Stephen||Zhou, Beiyan