Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata
Filip K. Swirski, … , Ralph Weissleder, Mikael J. Pittet
Filip K. Swirski, … , Ralph Weissleder, Mikael J. Pittet
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):195-205. https://doi.org/10.1172/JCI29950.
View: Text | PDF
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

×

Figure 2

Peripheral blood monocytosis develops over the course of 250 days on an atherogenic diet.

Options: View larger image (or click on image) Download as PowerPoint
Peripheral blood monocytosis develops over the course of 250 days on an ...
(A) Number of total monocytes and Ly-6Chi and Ly-6Clo subtypes in bone marrow, blood, and spleens of apoE–/– mice at various days of Western diet. Statistical analysis was based on an exponential growth curve and known cell numbers on day 0. Curve fit (solid line) and 95% confidence intervals (dashed lines) are shown. Doubling time (DT) of cell number is shown. (B) The same analysis was conducted with peripheral blood from apoE+/+ and apoE–/– mice that remained on chow diet. Doubling time of cell number in days is shown. (C) Splenic CD11bhiCD90loB220loCD49bloNK1.1loLy-6Glo cells were divided into F4/80hiCD11chiI-Ab–high macrophages/dendritic cells (gate i) and F4/80loCD11cloI-Ab–low monocytes, which were further divided into Ly-6Clo (gate ii) and Ly-6Chi (gate iii) subsets. These 3 subsets were isolated and stained with HEMA 3 for microscopic analysis. Scale bar: 10 μm. Results are pooled from 8 independent experiments.