Cited by 438Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismCerebrovascular and Carotid Artery Diseases

Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine Models

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Kim, Kyeongdae, Shim, Dahee, Lee, Jun Seong, Zaitsev, Konstantin, Williams, Jesse W., Kim, Ki-Wook, Jang, Man-Young, Seok Jang, Hyung +15 more·2018·Circulation Research

Abstract

Rationale: Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during atherosclerosis. Objective: We sought to examine the transcriptomic profiles of foamy and nonfoamy macrophages isolated from atherosclerotic intima. Methods and Results: Single-cell RNA sequencing analysis of CD45 + leukocytes from murine atherosclerotic aorta revealed that there are macrophage subpopulations with distinct differentially expressed genes involved in various functional pathways. To specifically characterize the intimal foamy macrophages of plaque, we developed a lipid staining–based flow cytometric method for analyzing the lipid-laden foam cells of atherosclerotic aortas. We used the fluorescent lipid probe BODIPY493/503 and assessed side-scattered light as an indication of cellular granularity. BODIPY hi SSC hi foamy macrophages were found residing in intima and expressing CD11c. Foamy macrophage accumulation determined by flow cytometry was positively correlated with the severity of atherosclerosis. Bulk RNA sequencing analysis showed that compared with nonfoamy macrophages, foamy macrophages expressed few inflammatory genes but many lipid-processing genes. Intimal nonfoamy macrophages formed the major population expressing IL (interleukin)-1β and many other inflammatory transcripts in atherosclerotic aorta. Conclusions: RNA sequencing analysis of intimal macrophages from atherosclerotic aorta revealed that lipid-loaded plaque macrophages are not likely the plaque macrophages that drive lesional inflammation.

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Crossref · 10.1161/circresaha.118.312804

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  • Lack of classical pro-inflammatory signaling has been previously found in MS lesions by mass cytometry of microglia and matches the lipid-induced lysosomal phenotype described in other diseases.

    “This lack of classical pro-inflammatory signaling has been previously found in MS lesions by mass cytometry of microglia49 and matches the lipid-induced lysosomal phenotype described in other diseases14,18,50,51.”
  • Overloading macrophages with cytoplasmic cholesteryl ester droplets shifts their phenotype from highly pro-inflammatory to fat-storing with less pro-inflammatory potential, as supported by murine atherosclerosis models.

    “The concept that overloading macrophages with cytoplasmic cholesteryl ester droplets (that is, their transformation into foam cells) shifts the macrophage phenotype from highly pro-inflammatory to fat-storing with less pro-inflammatory potential has received strong support in the past year by elegant results obtained in murine models of atherosclerosis152.”

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Authors
Kim, K., Shim, D., Lee, J. S., Zaitsev, K., Williams, J. W., Kim, K.-W., Jang, M.-Y., Seok Jang, H., Yun, T. J., Lee, S. H., Yoon, W. K., Prat, A., Seidah, N. G., Choi, J., Lee, S.-P., Yoon, S.-H., Nam, J. W., Seong, J. K., Oh, G. T., Randolph, G. J., Artyomov, M. N., Cheong, C., & Choi, J.-H.
Affiliations
  • Washington University in St. Louis (US)
  • Hanyang University (KR)
  • Montreal Clinical Research Institute (CA)
  • ITMO University (RU)
  • From the Department of Life Sciences (K.K., D.S., M.-Y.J., H.S.J., S.H.L., S.-H.Y., J.W.N., J.-H.C.), College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea
  • Seoul National University (KR)
  • Korea Research Institute of Bioscience and Biotechnology (KR)
  • Ewha Womans University (KR)
Corresponding author
  • Kim, Kyeongdae
  • Shim, Dahee
  • Lee, Jun Seong
  • Zaitsev, Konstantin
  • Randolph, Gwendalyn J.
  • Artyomov, Maxim N.
  • Cheong, Cheolho
  • Choi, Jae-Hoon
Venue
Circulation Research
Published
2018-10-26
Volume
123
Issue
10
Pages
1127-1142
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
OpenAlex
W2891644675
Cited by
434
References
52
Citations by year
2026: 36 · 2025: 57 · 2024: 69 · 2023: 60 · 2022: 71 · 2021: 57 · 2020: 42 · 2019: 37 · 2018: 5
FWCI
15.15
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • KRIBB Repository (submittedVersion)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders
  • Hanyang University
  • National Institutes of Health (UL1TR002345)
  • Canadian Institutes of Health Research (125933_1, 148363)
  • National Heart, Lung, and Blood Institute (K99HL138163)
  • National Cancer Institute (P30CA091842)
  • National Institute of Allergy and Infectious Diseases (U01AI025903, R37AI049653)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DP1DK109668)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
Keywords
atherosclerosis, plaque macrophages, foam cells, macrophage heterogeneity, IL-1β, aortic intima, BODIPY staining, single-cell RNA sequencing
MeSH terms
Animals, Aorta, Cells, Cultured, Humans, Macrophages, Male, Mice, Inbred C57BL, Mice, Plaque, Atherosclerotic, Transcriptome

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