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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

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 7

Role of CCR5 in monocyte migration into plaques.

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Role of CCR5 in monocyte migration into plaques.
(A) Blood monocyte subs...
(A) Blood monocyte subsets were stained for CCR5 expression in apoE–/– mice. Bold line, staining with anti-CCR5 mAb; thin line, isotype control staining. (B) apoE–/– mice were treated i.v. with latex to label Ly-6Clo monocytes. The mean number of latex+ cells in lesion sections collected along the entire aortic arch of apoE–/– mice treated with control mAb or anti-CCR5 was determined by an observer blinded to the experimental protocol. Each data point represents analysis of an individual mouse. Differences between control and anti-CCR5 were significant; P < 0.01. (C) An analysis similar to that represented in B, except apoE–/– mice were treated so that Ly-6Chi monocytes were latex+ during the assay. Differences between control and anti-CCR5 were significant; P < 0.04.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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