Meta-analysis of leukocyte diversity in atherosclerotic mouse aortas

Alma Zernecke, Holger Winkels, Clément Cochain, Jesse W. Williams, Dennis Wolf, Oliver Soehnlein, Clint S. Robbins, Claudia Monaco, Inhye Park, Coleen A. McNamara, Christoph J. Binder, Myron I. Cybulsky, Corey A. Scipione, Catherine C. Hedrick, Elena V. Galkina, Tin Kyaw, Yanal Ghosheh, Huy Q. Dinh, Klaus Ley

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations

Abstract

The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets - resident, inflammatory, interferon-inducible cell, and Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages - and identify a new macrophage subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2, and CD (cluster of differentiation)-8 T cells form prominent and separate immune cell populations in atherosclerotic aortas. Many CD4 T cells express IL (interleukin)-17 and the chemokine receptor CXCR (C-X-C chemokine receptor)-6. A small number of regulatory T cells and T helper 1 cells is also identified. Immature and naive T cells are present in both healthy and atherosclerotic aortas. Our meta-analysis overcomes limitations of individual studies that, because of their experimental approach, over- or underrepresent certain cell populations. Mass cytometry studies demonstrate that cell surface phenotype provides valuable information beyond the cell transcriptomes. The present analysis helps resolve some long-standing controversies in the field. First, Trem2+foamy macrophages are not proinflammatory but interferon-inducible cell and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, Pf4, which had been considered specific for platelets and megakaryocytes, is also prominently expressed in the main population of resident vascular macrophages. Fourth, a new type of resident macrophage shares transcripts with cavity macrophages. Finally, the discovery of a prominent innate lymphoid cell-2 cluster links the single-cell RNA sequencing work to recent flow cytometry data suggesting a strong atheroprotective role of innate lymphoid cells-2. This resolves apparent discrepancies regarding the role of T helper 2 cells in atherosclerosis based on studies that predated the discovery of innate lymphoid cells-2 cells.

Original languageEnglish (US)
Pages (from-to)402-426
Number of pages25
JournalCirculation research
Volume127
Issue number3
DOIs
StatePublished - Jul 17 2020

Bibliographical note

Funding Information:
O. Soehnlein has consulted for Novo Nordisk and AstraZeneca, has received a grant from Novo Nordisk to study the effect of circadian rhythms on atherosclerosis, and holds a patent on targeting histones in cardiovascular inflammation. K. Ley has received research grants from Novo Nordisk and Kirin Pharmaceuticals. The other authors report no conflicts.

Funding Information:
A. Zernecke was supported by the Interdisciplinary Center for Clinical Research (Interdisziplinäres Zentrum für Klinische Forschung [IZKF]), University Hospital Würzburg (E-352 and A-384), and the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation, 374031971 - TRR 240, 324392634 - TR221, ZE827/13-1, 14-1, 15-1, and 16-1). H. Winkels was supported by the DFG (WI 4811/1-1 and DFG-SFB TRR259 A04). C. Cochain was supported by the Interdisciplinary Center for Clinical Research (IZKF), University Hospital Würzburg (E-353), the German Ministry of Research and Education within the Comprehensive Heart Failure Centre Würzburg (BMBF 01EO1504), the DFG (CO1220/1-1). C.S. Robbins was supported by CIHR awards (376108 and 426699) and the Peter Munk Chair in Aortic Disease Research. C. Monaco was supported by the European Commission under the Seventh Framework Programme (grant agreement n° 201668 [Athero-Remo], FP7/2007-2013; grant agreement n°HEALTH-F2-2013-602114 [Athero-B-Cell], grant agreement n° HEALTH-F2-2013-602222 [Athero-Flux]), and H2020 (EU H2020 H2020-SC1-2016-2017—TAXINOMISIS); The British Heart Foundation, The Kennedy Trustees, and the Novo Nordisk Foundation (Grant number NNF15CC0018346). H.Q. Dinh and C.C. Hedrick were supported by NIH P01 HL136275, NIH P01 HL055798, NIH R01 HL134236, and NIH R01 CA202987. D. Wolf has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 853425). O. Soehnlein was supported by the Else-Kröner-Fresenius Stiftung, the Leducq Foundation, the Vetenskapsrådet (2017-01762), and the DFG (SO876/11-1, SFB914 TP B8, SFB1123 TP A6 and TP B5). C.A. McNamara was supported by 1R01HL 136098-01 and P01 HL136275-01. C.J. Binder was supported by the Austrian Science Fund (FWF [Fonds zur Förderung der wissenschaftlichen Forschung], SFB InThro F54). M.I. Cybulsky was supported by the Canadian Institutes of Health Research (FDN-154299). E.V. Galkina was

Funding Information:
supported by NIH R01HL139000. K. Ley was supported by NIH HL 136275, 140976, 145241, 146134, and 148094.

Keywords

  • T lymphocytes
  • atherosclerosis
  • interferons
  • macrophages
  • monocytes
  • mouse
  • neutrophils

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