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Cited by 53Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismMicroRNA in disease regulation

miR-33 Silencing Reprograms the Immune Cell Landscape in Atherosclerotic Plaques

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Afonso, Milessa Silva, Sharma, Monika, Schlegel, Martin, van Solingen, Coen, Koelwyn, Graeme J., Shanley, Lianne C., Beckett, Lauren, Peled, Daniel +7 more·2021·Circulation Research
DOI 10.1161/circresaha.120.317914PMC PMC8049965
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Abstract

Rationale: MicroRNA-33 (miR-33 [post-transcriptionally in the rationale]) post-transcriptionally represses genes involved in lipid metabolism and energy homeostasis. Targeted inhibition of miR-33 increases plasma HDL (high-density lipoprotein) cholesterol and promotes atherosclerosis regression, in part, by enhancing reverse cholesterol transport and dampening plaque inflammation. However, how miR-33 reshapes the immune microenvironment of plaques remains poorly understood. Objective: To define how miR-33 inhibition alters the dynamic balance and transcriptional landscape of immune cells in atherosclerotic plaques. Methods and Results: We used single-cell RNA-sequencing of aortic CD45 + cells, combined with immunohistologic, morphometric, and flow cytometric analyses to define the changes in plaque immune cell composition, gene expression, and function following miR-33 inhibition. We report that anti–miR-33 treatment of Ldlr –/– mice with advanced atherosclerosis reduced plaque burden and altered the plaque immune cell landscape by shifting the balance of proatherosclerotic and antiatherosclerotic macrophage and T-cell subsets. By quantifying the kinetic processes that determine plaque macrophage burden, we found that anti–miR-33 reduced levels of circulating monocytes and splenic myeloid progenitors, decreased macrophage proliferation and retention, and promoted macrophage attrition by apoptosis and efferocytotic clearance. Single-cell RNA-sequencing of aortic arch plaques showed that anti–miR-33 reduced the frequency of MHCII hi (major histocompatibility complex II) inflammatory and Trem2 hi (Triggering Receptor Expressed On Myeloid Cells 2) metabolic macrophages, but not tissue-resident macrophages. Furthermore, anti–miR-33 led to derepression of distinct miR-33 target genes in the different macrophage subsets: in resident and Trem2 hi macrophages, anti–miR-33 relieved repression of miR-33 target genes involved in lipid metabolism (eg, Abca1 , Ncoa1, Ncoa2 , Crot ), whereas in MHCII hi macrophages, anti–miR-33 upregulated target genes involved in chromatin remodeling and transcriptional regulation. Anti–miR-33 also reduced the accumulation of aortic CD8+ T cells and CD4+ T-helper 1 cells, and increased levels of FoxP3+ (Forkhead Box P3) regulatory T cells in plaques, consistent with an immune-dampening effect on plaque inflammation. Conclusions: Our results provide insight into the immune mechanisms and cellular players that execute anti–miR-33’s atheroprotective actions in the plaque.

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  • Single-cell analyses have confirmed anti-inflammatory and profibrotic effects in macrophages, which can contribute to atheroprotective effects and plaque stabilization.

    “Single-cell analyses have confirmed their anti-inflammatory and profibrotic effects in macrophages, which can contribute to atheroprotective effects and plaque stabilization 30 , 31) .”

    From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [30]

    The Results and Discussion (pages unavailable) link single-cell analysis of anti-miR-33-treated mouse plaques to reduced inflammatory macrophage signatures, increased tissue-reparative macrophage markers, and atheroprotective effects. They do not establish a profibrotic effect or demonstrate plaque stabilization; the reported outcomes include increased efferocytosis and reduced necrotic area. (LLM, conf=0.86)

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Authors
Afonso, M. S., Sharma, M., Schlegel, M., van Solingen, C., Koelwyn, G. J., Shanley, L. C., Beckett, L., Peled, D., Rahman, K., Giannarelli, C., Li, H., Brown, E. J., Khodadadi-Jamayran, A., Fisher, E. A., & Moore, K. J.
Affiliations
  • New York University (US)
  • Department of Medicine, Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine (M.S.A., M. Sharma, M. Schlegel, C.v.S., G.J.K., L.C.S., L.B., D.P., K.R., E.J.B., E.A.F., K.J.M.).
  • Icahn School of Medicine at Mount Sinai (US)
  • Applied Bioinformatics Laboratories (A.K.-J.), New York University School of Medicine.
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-04-16
Volume
128
Issue
8
Pages
1122-1138
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.120.317914
PMC
PMC8049965
OpenAlex
W3129455797
Cited by
53
References
14
Citations by year
2026: 8 · 2025: 5 · 2024: 12 · 2023: 11 · 2022: 17
FWCI
3.73
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Funders
  • HHS | NIH | National Heart, Lung, and Blood Institute (R35HL135799, R01HL084312, P01HL131481, P01HL131478, T32HL098129, R01HL153712)
  • American Heart Association (19POST34380010, 14Post20180018, 19CDA34630066, 20SFRN35210252)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Keywords
miR-33, atherosclerosis, macrophage polarization, TREM2, MHC class II, CD8+ T cells, Th1 cells, CD4+ T cells, efferocytosis, monocyte recruitment, Ldlr-deficient mice, lipid metabolism, chromatin remodeling
MeSH terms
Animals, Macrophages, Male, Mice, Inbred C57BL, Monocytes, T-Lymphocytes, MicroRNAs, Lipid Metabolism, Mice, Plaque, Atherosclerotic, Transcriptome

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