Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas Article

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.

authors

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

publication date

  • 2020

webpage

published in

number of pages

  • 24

start page

  • 402

end page

  • 426

volume

  • 127

issue

  • 3