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Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques
Frank Tacke, … , Andreas J. Habenicht, Gwendalyn J. Randolph
Frank Tacke, … , Andreas J. Habenicht, Gwendalyn J. Randolph
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):185-194. https://doi.org/10.1172/JCI28549.
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Research Article Article has an altmetric score of 18

Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques

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Abstract

Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2+CX3CR1+Ly-6Chi and CCR2–CX3CR1++Ly-6Clo monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X3-C motif chemokine receptor 1 (CX3CR1) are linked to progression of atherosclerotic plaques. Here, we analyzed mouse monocyte subsets in apoE-deficient mice and traced their differentiation and chemokine receptor usage as they accumulated within atherosclerotic plaques. Blood monocyte counts were elevated in apoE–/– mice and skewed toward an increased frequency of CCR2+Ly-6Chi monocytes in apoE–/– mice fed a high-fat diet. CCR2+Ly-6Chi monocytes efficiently accumulated in plaques, whereas CCR2–Ly-6Clo monocytes entered less frequently but were more prone to developing into plaque cells expressing the dendritic cell–associated marker CD11c, indicating that phagocyte heterogeneity in plaques is linked to distinct types of entering monocytes. CCR2– monocytes did not rely on CX3CR1 to enter plaques. Instead, they were partially dependent upon CCR5, which they selectively upregulated in apoE–/– mice. By comparison, CCR2+Ly-6Chi monocytes unexpectedly required CX3CR1 in addition to CCR2 and CCR5 to accumulate within plaques. In many other inflammatory settings, these monocytes utilize CCR2, but not CX3CR1, for trafficking. Thus, antagonizing CX3CR1 may be effective therapeutically in ameliorating CCR2+ monocyte recruitment to plaques without impairing their CCR2-dependent responses to inflammation overall.

Authors

Frank Tacke, David Alvarez, Theodore J. Kaplan, Claudia Jakubzick, Rainer Spanbroek, Jaime Llodra, Alexandre Garin, Jianhua Liu, Matthias Mack, Nico van Rooijen, Sergio A. Lira, Andreas J. Habenicht, Gwendalyn J. Randolph

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Figure 4

Tracing recruitment of monocyte subsets in atherosclerotic plaques.

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Tracing recruitment of monocyte subsets in atherosclerotic plaques.
(A) ...
(A) Representative photomicrograph of a lesional section from a 7-month-old apoE–/– mouse where latex+Ly-6Chi monocyte-derived cells were observed. Red: CD68+ cells; blue: DAPI-stained nuclei; green: latex beads (internal elastic lamina is also green due to autofluorescence). Arrows indicate the presence of latex+ cells within the lesion section. lu, lumen of aorta. Original magnification, ×260. (B) Quantification of the recruitment of apoE–/– Ly-6Chi and Ly-6Clo monocyte subsets into lesions 1, 3, or 5 days after subset labeling in age-matched apoE–/– mice (7 months) maintained on a chow diet. Mean number of latex+ cells per lesion section is shown on the left, and normalized data that accounts for the differences in frequency of latex+ monocyte subsets over time are shown on the right. (C) The effect of feeding a high-fat/high-cholesterol diet on the accumulation of apoE–/– monocyte subsets into plaques 5 days after latex labeling. Mean number of latex+ cells per lesion section is shown on the left, and normalized data that accounts for the differences in frequency of latex+ monocyte subsets in response to diet are shown on the right. For all data points, 5–8 mice were studied.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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