Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata
Filip K. Swirski, Peter Libby, Elena Aikawa, Pilar Alcaide, F. William Luscinskas, Ralph Weissleder, Mikael J. Pittet
Filip K. Swirski, Peter Libby, Elena Aikawa, Pilar Alcaide, F. William Luscinskas, Ralph Weissleder, Mikael J. Pittet
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Research Article

Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata

Abstract

Macrophage accumulation participates decisively in the development and exacerbation of atherosclerosis. Circulating monocytes, the precursors of macrophages, display heterogeneity in mice and humans, but their relative contribution to atherogenesis remains unknown. We report here that the Ly-6Chi monocyte subset increased dramatically in hypercholesterolemic apoE–deficient mice consuming a high-fat diet, with the number of Ly-6Chi cells doubling in the blood every month. Ly-6Chi monocytes adhered to activated endothelium, infiltrated lesions, and became lesional macrophages. Hypercholesterolemia-associated monocytosis (HAM) developed from increased survival, continued cell proliferation, and impaired Ly-6Chi to Ly-6Clo conversion and subsided upon statin-induced cholesterol reduction. Conversely, the number of Ly-6Clo cells remained unaffected. Thus, we believe that Ly-6Chi monocytes represent a newly recognized component of the inflammatory response in experimental atherosclerosis.

Authors

Filip K. Swirski, Peter Libby, Elena Aikawa, Pilar Alcaide, F. William Luscinskas, Ralph Weissleder, Mikael J. Pittet

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Figure 1

Hypercholesterolemia induces peripheral blood Ly-6Chi monocytosis.

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Hypercholesterolemia induces peripheral blood Ly-6Chi monocytosis. ...
(A) Mononuclear cells from blood of apoE+/+ and apoE–/– mice consuming either chow or Western diet were stained with anti-CD11b, -CD90, -B220, -CD49b, -NK1.1, –Ly-6G, and –Ly-6C mAbs. Living cells were gated to determine presence and percentage of CD11bhiCD90loB220loCD49bloNK1.1loLy-6Glo monocytes (top row) and further divided into Ly-6Chi and Ly-6Clo subsets (bottom row). Representative dot plots and histograms from individual mice are depicted. Percentages of cells are shown as mean ± SEM. (B) Total blood monocytes in apoE+/+ and apoE–/– mice consuming either Western diet (+) or chow (–). (C) Total blood Ly-6Chi monocytes. (D) Total blood Ly-6Clo monocytes. (E) Total peripheral blood leukocytes. (F) Representative dot plots depicting expression of CD62L and CD11c among Ly-6Chi and Ly-6Clo monocytes. Percentages of cells in each quadrant are shown as mean ± SEM. (G) Representative cytospin preparations of purified blood Ly-6Chi and Ly-6Clo monocytes in apoE+/+ mice on chow and apoE–/– mice on Western diet. Scale bar: 10 μm. Student’s t test was used. Results are representative of 8 independent experiments with 5–14 mice per group.