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Cited by 97Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismNitric Oxide and Endothelin Effects

LXRα Regulates Macrophage Arginase 1 Through PU.1 and Interferon Regulatory Factor 8

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Pourcet, Benoit, Feig, Jonathan E., Vengrenyuk, Yuliya, Hobbs, Adrian J., Kepka-Lenhart, Diane, Garabedian, Michael J., Morris, Sidney M., Fisher, Edward A. +1 more·2011·Circulation Research
DOI 10.1161/circresaha.111.241810PMC PMC3180895
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Abstract

Rationale: Activation of liver X receptors (LXRs) inhibits the progression of atherosclerosis and promotes regression of existing lesions. In addition, LXRα levels are high in regressive plaques. Macrophage arginase 1 (Arg1) expression is inversely correlated with atherosclerosis progression and is markedly decreased in foam cells within the lesion. Objective: To investigate LXRα regulation of Arg1 expression in cultured macrophages and atherosclerotic regressive lesions. Methods and Results: We found that Arg1 expression is enhanced in CD68+ cells from regressive versus progressive lesions in a murine aortic arch transplant model. In cultured macrophages, ligand-activated LXRα markedly enhances basal and interleukin-4–induced Arg1 mRNA and protein expression as well as promoter activity. This LXRα-enhanced Arg1 expression correlates with a reduction in nitric oxide levels. Moreover, Arg1 expression within regressive atherosclerotic plaques is LXRα-dependent, as enhanced expression of Arg1 in regressive lesions is impaired in LXRα-deficient CD68+ cells. LXRα does not bind to the Arg1 promoter but instead promotes the interaction between PU.1 and interferon regulatory factor (IRF)8 transcription factors and induces their binding of a novel composite element. Accordingly, knockdown of either IRF8 or PU.1 strongly impairs LXRα regulation of Arg1 expression in macrophage cells. Finally, we demonstrate that LXRα binds the IRF8 locus and its activation increases IRF8 mRNA and protein levels in these cells. Conclusions: This work implicates Arg1 in atherosclerosis regression and identifies LXRα as a novel regulator of Arg1 and IRF8 in macrophages. Furthermore, it provides a unique molecular mechanism by which LXRα regulates macrophage target gene expression through PU.1 and IRF8.

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References 50 · Cited by 97

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Authors
Pourcet, B., Feig, J. E., Vengrenyuk, Y., Hobbs, A. J., Kepka-Lenhart, D., Garabedian, M. J., Morris, S. M., Fisher, E. A., & Pineda-Torra, I.
Affiliations
  • From the Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom (B.P., I.P.-T.); the Department of Medicine (Cariology) and the Marc and Ruti Bell Program in Vascular Biology (J.E.F., Y.V., E.A.F.), and the Department of Microbiology (M.J.G.), New York University School of Medicine, New York, NY; Pharmacology (NPP), University College London, London, United Kingdom (A.J.H.); and the Department of Microbiology and Molecular Genetics, University of...
  • University of Pittsburgh (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2011-08-19
Volume
109
Issue
5
Pages
492-501
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.111.241810
PMC
PMC3180895
OpenAlex
W2161118947
Cited by
97
References
50
Citations by year
2026: 6 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 1 · 2021: 6 · 2020: 6 · 2019: 2 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 8 · 2014: 4 · 2013: 12 · 2012: 14
FWCI
4.40
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (NIH-R01)
  • U.S. Public Health Service (R01-084312)
  • Medical Research Council (G0801278)
  • National Institute on Aging (AG-029748, F30AG029748)
  • National Heart, Lung, and Blood Institute (R01HL084312, T32HL098129)
  • National Institute of General Medical Sciences (R01GM57384, R01GM057384)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
liver X receptor alpha, arginase-1, macrophages, PU.1, IRF8, atherosclerosis regression, foam cells, nitric oxide, transcriptional regulation, IL-4
MeSH terms
Liver X Receptors, Interferon Regulatory Factor-8, Proto-Oncogene Protein Spi-1, Animals, Arginase, Cell Line, Macrophages, Protein Binding, Proto-Oncogene Proteins, Trans-Activators, Mice, Knockout, Gene Targeting, Atherosclerosis, Interferon Regulatory Factors, Mice, Genetic Loci, Orphan Nuclear Receptors

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