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Cited by 91Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis

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Chen, Hsiao-Huei, Keyhanian, Kianoosh, Zhou, Xun, Vilmundarson, Ragnar O., Almontashiri, Naif A.M., Cruz, Shelly A., Pandey, Nihar R., Lerma Yap, Nida +8 more·2015·Circulation Research
DOI 10.1161/circresaha.114.305777
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Abstract

Rationale: Inflammation impairs macrophage cholesterol clearance from vascular tissues and promotes atherosclerosis. Inflammatory macrophages suppress expression of the transcription cofactor interferon regulatory factor 2–binding protein 2 (IRF2BP2), and genetic variants near IRF2BP2 associate with ischemic heart disease progression in humans. Objectives: To test whether IRF2BP2 in macrophages affects atherosclerosis in mice and humans. Methods and Results: We generated mice that delete IRF2BP2 in macrophages. IRF2BP2-deficient macrophages worsened atherosclerosis in irradiated low-density lipoprotein receptor null-recipient mice and in apolipoprotein E null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux because of their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor Krüppel-like factor 2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of Krüppel-like factor 2. Importantly, restoring Krüppel-like factor 2 in IRF2BP2-deficient macrophages attenuated M1 inflammatory and rescued M2 anti-inflammatory gene activation and improved the cholesterol efflux deficit by restoring ABCA1 activation in response to cholesterol loading. In a cohort of 1066 angiographic cases and 1011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3′ untranslated region sequence of human IRF2BP2 mRNA had a higher risk of coronary artery disease (recessive model, odds ratio [95% confidence interval]=1.560 [1.179–2.065], P =1.73E-03) and had lower IRF2BP2 (and Krüppel-like factor 2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies. Conclusion: Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans.

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  • Notable perturbation-specific gene ontology terms include ribosome assembly (SETD5), mitochondrion organization (FOXP1), lipid homoeostasis (IRF2BPL), autophagosome maturation (KAT2B), and cilium development (MECP2).

    “Some notable examples include the gene ontology terms ribosome assembly (SETD5 perturbation)36, mitochondrion organization (FOXP1 perturbation)37, lipid homoeostasis (IRF2BPL perturbation)38, autophagosome maturation (KAT2B perturbation)39 and cilium development (MECP2 perturbation)40.”

    From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [38]

    The section “IRF2BP2-Deficient Macrophages Have an Increased Propensity for Foam Cell Formation” (page unavailable) reports altered lipid accumulation, cholesterol uptake, and cholesterol efflux after IRF2BP2 deletion. That supports a link between IRF2BP2 perturbation and lipid handling, but the cited paper does not establish the claimed lipid-homoeostasis gene ontology term for IRF2BPL perturbation; IRF2BPL is a different gene. (LLM, conf=0.86)

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Authors
Chen, H.-H., Keyhanian, K., Zhou, X., Vilmundarson, R. O., Almontashiri, N. A. M., Cruz, S. A., Pandey, N. R., Lerma Yap, N., Ho, T., Stewart, C. A., Huang, H., Hari, A., Geoffrion, M., McPherson, R., Rayner, K. J., & Stewart, A. F. R.
Affiliations
  • University of Ottawa (CA)
  • From the Department of Cellular and Molecular Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (H.-H.C., K.K., X.Z., S.A.C., N.R.P., C.A.S., H.H., A.H.); the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, and the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.O.V., N.A.M.A., N.L.Y., T.H., M.G., R.M., K.J.R., A.F.R.S.); and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (H.H.C.,...
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2015-09-25
Volume
117
Issue
8
Pages
671-683
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.114.305777
OpenAlex
W2122547951
Cited by
91
References
3
Citations by year
2026: 3 · 2025: 7 · 2024: 7 · 2023: 5 · 2022: 11 · 2021: 19 · 2020: 9 · 2019: 12 · 2018: 3 · 2017: 7 · 2016: 4 · 2015: 3
FWCI
2.79
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Heart and Stroke Foundation of Canada
  • University of Ottawa
  • Taibah University
  • Canadian Institutes of Health Research
  • Natural Sciences and Engineering Research Council of Canada
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
IRF2BP2, macrophage inflammation, atherosclerosis, cholesterol efflux, ABCA1, KLF2, MEF2, coronary artery disease, 3' untranslated region polymorphism, ischemic heart disease, macrophage polarization, LDL receptor-null mice, apolipoprotein E-null mice
MeSH terms
Aged, Aged, 80 and over, Animals, Apolipoproteins E, Carrier Proteins, Cells, Cultured, Cholesterol, Coronary Artery Disease, Disease Models, Animal, DNA-Binding Proteins, Female, Homozygote, Humans, Inflammation, Macrophage Activation, Macrophages, Male, Mice, Inbred C57BL, Middle Aged, Nuclear Proteins, Phenotype, Polymorphism, Genetic, Promoter Regions, Genetic, Radiography, Receptors, LDL, Risk Factors, Transcription Factors, Transfection, Odds Ratio, Case-Control Studies, Mice, Knockout, Genetic Predisposition to Disease, 3' Untranslated Regions, Atherosclerosis, Kruppel-Like Transcription Factors, ATP Binding Cassette Transporter 1, MEF2 Transcription Factors, Protective Factors

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