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Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine Models
Open accessAbstract
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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“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.”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [51]
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“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.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [152]
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Metadata
- 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
- ORCID
- Venue
- Circulation Research
- Published
- 2018-10-26
- Volume
- 123
- Issue
- 10
- Pages
- 1127-1142
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC6945121
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular 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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