The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.
MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis
Open accessAbstract
Cellular metabolism is increasingly recognized as a controller of immune cell fate and function. MicroRNA-33 (miR-33) regulates cellular lipid metabolism and represses genes involved in cholesterol efflux, HDL biogenesis, and fatty acid oxidation. Here, we determined that miR-33-mediated disruption of the balance of aerobic glycolysis and mitochondrial oxidative phosphorylation instructs macrophage inflammatory polarization and shapes innate and adaptive immune responses. Macrophage-specific Mir33 deletion increased oxidative respiration, enhanced spare respiratory capacity, and induced an M2 macrophage polarization-associated gene profile. Furthermore, miR-33-mediated M2 polarization required miR-33 targeting of the energy sensor AMP-activated protein kinase (AMPK), but not cholesterol efflux. Notably, miR-33 inhibition increased macrophage expression of the retinoic acid-producing enzyme aldehyde dehydrogenase family 1, subfamily A2 (ALDH1A2) and retinal dehydrogenase activity both in vitro and in a mouse model. Consistent with the ability of retinoic acid to foster inducible Tregs, miR-33-depleted macrophages had an enhanced capacity to induce forkhead box P3 (FOXP3) expression in naive CD4(+) T cells. Finally, treatment of hypercholesterolemic mice with miR-33 inhibitors for 8 weeks resulted in accumulation of inflammation-suppressing M2 macrophages and FOXP3(+) Tregs in plaques and reduced atherosclerosis progression. Collectively, these results reveal that miR-33 regulates macrophage inflammation and demonstrate that miR-33 antagonism is atheroprotective, in part, by reducing plaque inflammation by promoting M2 macrophage polarization and Treg induction.
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“Inhibition of miR-33a or miR-33a deletion in macrophages has been shown to affect myeloid cell differentiation 25) , induce M2 macrophage polarization with mitochondrial respiratory and metabolic changes 26 , 27) , and enhance autophagy 28 , 29) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [26]
In the citing paper
“several studies have found that antagonism of miR-33 can reduce atherosclerotic plaque burden (Karunakaran et al., 2015; Ouimet et al., 2015; Rayner et al., 2011b; Rotllan et al., 2013).”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Ouimet et al., 2015
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“Expression of miR-33 is also overexpressed in M1, thus promoting pro-inflammatory functions [132].”
From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [132]
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Cites
Macrophage biology in development, homeostasis and disease
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“In addition, macrophages play important roles in tissue homeostasis and resolution of inflammation (2).”
AMPK: a nutrient and energy sensor that maintains energy homeostasis
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Succinate is an inflammatory signal that induces IL-1β through HIF-1α
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Self-citationMacrophages in atherosclerosis: a dynamic balance
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Self-citationMetabolic control through the PGC-1 family of transcription coactivators
Lin, J., Handschin, C., & Spiegelman, B. M. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.004 · Cited by 2,130 · cited 1×
“…malonyl-CoA–mediated inhibition of CPT1 and stimulating uptake of activated fatty acids into the mitochondria (44, 45), and (b) enhancement of expression of SIRT1 and PGC-1 α , resulting in transcriptional activation of genes involved in mitochondrial FAO and mitochondrial biogenesis (46, 47).”
Michalek, R. D., Gerriets, V. A., Jacobs, S. R., Macintyre, A. N., MacIver, N. J., Mason, E. F., Sullivan, S. A., Nichols, A. G., & Rathmell, J. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003613 · Cited by 2,091
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Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation
Vats, D., Mukundan, L., Odegaard, J. I., Zhang, L., Smith, K. L., Morel, C. R., Greaves, D. R., Murray, P. J., & Chawla, A. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.011 · Cited by 1,369
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Murray, P. J. (2017) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034339 · Cited by 2,981
Pathophysiology of Atherosclerosis
Jebari‐Benslaiman, S., Galicia-García, U., Larrea, A., Olaetxea, J. R., Alloza, I., Vandenbroeck, K., Benito‐Vicente, A., & Martı́n, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063346 · Cited by 1,166
Mitochondrial dysfunction prevents repolarization of inflammatory macrophages
Van den Bossche, J., Baardman, J., Otto, N. A., van der Velden, S., Neele, A. E., van den Berg, S. M., Luque-Martin, R., Chen, H.-J., Boshuizen, M. C. S., Ahmed, M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.008 · Cited by 1,027
HDL and Reverse Cholesterol Transport
Ouimet, M. I., Barrett, T. J., & Fisher, E. A. A. (2019) · Circulation Research · doi:10.1161/circresaha.119.312617 · Cited by 816
Self-citationAMP-activated protein kinase: the current landscape for drug development
Steinberg, G. R., & Carling, D. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0019-2 · Cited by 785
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Metadata
- Authors
- Ouimet, M., Ediriweera, H. N., Gundra, U. M., Sheedy, F. J., Ramkhelawon, B., Hutchison, S. B., Rinehold, K., van Solingen, C., Fullerton, M. D., Cecchini, K., Rayner, K. J., Steinberg, G. R., Zamore, P. D., Fisher, E. A., Loke, P., & Moore, K. J.
- Affiliations
- New York University (US)
- University of Ottawa (CA)
- Howard Hughes Medical Institute (US)
- McMaster University (CA)
- NYU Langone Health (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2015-10-26
- Volume
- 125
- Issue
- 12
- Pages
- 4334-4348
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4665799
- OpenAlex
- W2123366371
- Cited by
- 394
- References
- 67
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 27 · 2023: 37 · 2022: 24 · 2021: 45 · 2020: 45 · 2019: 46 · 2018: 35 · 2017: 47 · 2016: 33 · 2015: 1
- FWCI
- 19.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association (14POST20180018, 15POST25090199)
- NYU Langone Medical Center (P30CA016087)
- Canada Research Chairs
- National Institutes of Health (UL1TR000038, TR000038)
- Canadian Institutes of Health Research
- National Heart, Lung, and Blood Institute (R01HL084312, HL-084312, HL098055, P01HL098055, R01HL119047, R01HL108182, T32HL098129)
- National Cancer Institute (P30CA016087)
- National Institute of Allergy and Infectious Diseases (R21AI094166, R01AI093811, R01AI094166, T32AI007180)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- microRNA-33, macrophage polarization, M2 macrophages, atherosclerosis, aerobic glycolysis, mitochondrial oxidative phosphorylation, AMPK, ALDH1A2, retinoic acid, regulatory T cells, Foxp3, plaque inflammation, hypercholesterolemia, atheroprotection, lipid metabolism
- MeSH terms
- Aldehyde Dehydrogenase 1 Family, Aldehyde Dehydrogenase, Animals, Gene Expression Regulation, Glycolysis, Oxygen Consumption, Macrophages, Peritoneal, Mice, Knockout, MicroRNAs, Atherosclerosis, T-Lymphocytes, Regulatory, Retinal Dehydrogenase, Mice, Forkhead Transcription Factors, AMP-Activated Protein Kinases, Plaque, Atherosclerotic
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