Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models

Kyeongdae Kim, Dahee Shim, Jun Seong Lee, Konstantin Zaitsev, Jesse W. Williams, Ki Wook Kim, Man Young Jang, Hyung Seok Jang, Tae Jin Yun, Seung Hyun Lee, Won Kee Yoon, Annik Prat, Nabil G. Seidah, Jungsoon Choi, Seung Pyo Lee, Sang Ho Yoon, Jin Wu Nam, Je Kyung Seong, Goo Taeg Oh, Gwendalyn J. RandolphMaxim N. Artyomov, Cheolho Cheong, Jae Hoon Choi

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40 Scopus citations

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.

Original languageEnglish
Pages (from-to)1127-1142
Number of pages16
JournalCirculation Research
Volume123
Issue number10
DOIs
StatePublished - 2018 Jan 1

Keywords

  • Atherosclerosis
  • Flow cytometry
  • Foam cells
  • Macrophages
  • Mice
  • RNA-seq

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    Kim, K., Shim, D., Lee, J. S., Zaitsev, K., Williams, J. W., Kim, K. W., Jang, M. Y., Jang, H. S., 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., ... Choi, J. H. (2018). Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circulation Research, 123(10), 1127-1142. https://doi.org/10.1161/CIRCRESAHA.118.312804