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

Wei Ying, Alexander Tseng, Richard Cheng An Chang, Andrew Morin, Tyler Brehm, Karen Triff, Vijayalekshmi Nair, Guoqing Zhuang, Hui Song, Srikanth Kanameni, Haiqing Wang, Michael C. Golding, Fuller W. Bazer, Robert S. Chapkin, Stephen Safe, Beiyan Zhou

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

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 PPARy/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, PPARy directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARy binding 3 PPARy regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPARy-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 PPARy-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 PPARy/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.

Original languageEnglish (US)
Pages (from-to)4149-4159
Number of pages11
JournalJournal of Clinical Investigation
Volume125
Issue number11
DOIs
StatePublished - Nov 2 2015

ASJC Scopus subject areas

  • Medicine(all)

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