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Cited by 144Peroxisome Proliferator-Activated ReceptorsAdipokines, Inflammation, and Metabolic DiseasesImmune cells in cancer

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

Open access
Ying, Wei, Tseng, Alexander, Chang, Richard Cheng-An, Morin, Andrew, Brehm, Tyler, Triff, Karen, Nair, Vijayalekshmi, Zhuang, Guoqing +8 more·2015·Journal of Clinical Investigation
DOI 10.1172/jci81656PMC PMC4639972
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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 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.

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  • IL-4 and IL-13 activate PPARγ, which in turn activates transcription of miR-223, another marker of M2 polarization.

    “IL-4 and IL-13 activates PPARγ, which in turn activates transcription of miR-223—another marker of M2 polarization [197].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [197]

    The Introduction and the section on PPARγ regulation of miR-223 report that PPARγ directly promotes miR-223 expression; the results also show miR-223 induction in IL-4-stimulated M2 macrophages. The cited paper does not establish the full stated sequence in which both IL-4 and IL-13 activate PPARγ: the passages address IL-4, but not IL-13, and do not directly show IL-4 activating PPARγ. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Ying, W., Tseng, A., Chang, R. C.-A., Morin, A., Brehm, T., Triff, K., Nair, V., Zhuang, G., Song, H., Kanameni, S., Wang, H., Golding, M. C., Bazer, F. W., Chapkin, R. S., Safe, S., & Zhou, B.
Affiliations
  • Texas A&M University (US)
  • Texas A&M Health Science Center (US)
  • Wuhan University (CN)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2015-10-05
Volume
125
Issue
11
Pages
4149-4159
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci81656
PMC
PMC4639972
OpenAlex
W2125488249
Cited by
144
References
7
Citations by year
2026: 8 · 2025: 11 · 2024: 9 · 2023: 24 · 2022: 16 · 2021: 18 · 2020: 14 · 2019: 9 · 2018: 14 · 2017: 15 · 2016: 6
FWCI
5.07
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Journal of Clinical Investigation (publishedVersion, other-oa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Diabetes Association
  • American Heart Association
  • Texas AgriLife Research
  • National Institutes of Health
  • College of Veterinary Medicine and Biomedical Sciences, Texas A and M University
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098662)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
miR-223, PPARγ, macrophage polarization, alternative macrophage activation, adipose tissue macrophages, obesity, RASA1, NFAT5, M1 macrophage polarization, high-fat diet, miRNA target genes
MeSH terms
Pioglitazone, Animals, Bone Marrow, Gene Expression Regulation, Inflammation, Insulin Resistance, Macrophage Activation, Male, Mice, Inbred C57BL, Protein Binding, Transcription Factors, Stromal Cells, Gene Deletion, Adipocytes, Genes, Reporter, Mice, Knockout, Homeodomain Proteins, Th2 Cells, 3' Untranslated Regions, p120 GTPase Activating Protein, Gene Expression Profiling, MicroRNAs, Thiazolidinediones, Chromatin Immunoprecipitation, PPAR gamma, Intra-Abdominal Fat, Mice, Diet, High-Fat

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