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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.
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Research Article Article has an altmetric score of 23

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

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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 3

Ly-6Chi monocytosis results from increased survival, continued proliferation, and impaired Ly-6Chi to Ly-6Clo monocyte conversion.

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Ly-6Chi monocytosis results from increased survival, continued prolifera...
(A) Ly-6Chi monocytes from the spleens of apoE–/– mice were placed into culture with medium alone or medium supplemented with 100 μg/ml AcLDL or 50 μg/ml M-CSF. The percentage of cells alive 24 hours later was calculated based on the ratio of retrieved and input cell numbers. **P < 0.01, *P < 0.05 versus medium alone (1-way ANOVA with Tukey’s multiple comparison test). (B) apoE+/+ and apoE–/– mice on chow and Western diet received 3 i.p. injections of BrdU on 3 consecutive days. Cells from bone marrow, blood, and spleen were collected 1 day after the last injection and labeled with annexin V or anti-BrdU mAb. Results are shown for gated CD11bhiCD90loB220loCD49bloNK1.1loLy-6Glo monocytes as identified in Figure 1. Statistical analyses were performed using Student’s t test. (C) Representative dot plots depicting annexin V staining and BrdU incorporation in splenic CD11bhiCD90loB220loCD49bloNK1.1loLy-6Glo monocytes from apoE+/+ and apoE–/– mice on chow and Western diet. (D) apoE–/– mice on chow and Western diet received clodronate liposomes on day 0. Representative contour plots depict Ly-6C versus F4/80/I-Ab/CD11c phenotype among splenic CD11bhiCD90loB220loCD49bloNK1.1loLy-6Glo monocytes on days 1 and 5 or in age-matched untreated mice. (E) Percent of splenic Ly-6Clo monocytes recovered after clodronate liposome injection in apoE–/– mice on chow and Western diet compared with absolute number of cells in age-matched untreated mice. Shown are 1 of 2–3 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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