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

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 2

Recruitment of labeled WT monocytes to peripheral sites of acute inflammation.

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Recruitment of labeled WT monocytes to peripheral sites of acute inflamm...
Ly-6Clo or Ly-6Chi monocytes in WT mice were labeled with latex (24). (A) The appearance of latex+ cells in the peritoneal cavity was monitored by flow cytometry using F4/80 and CD115 antigens to identify monocytes and macrophages. Macrophages are seen as the prominent F4/80hi population in the noninflamed peritoneum (left dot plots). They become outnumbered by numerous infiltrating monocytes (inflamed plots; lower levels of F4/80 in lower right quadrants) and F4/80–CD115– neutrophils (inflamed plots; lower left quadrants). Note that Ly-6Chi labeling of monocytes leads to both latex+F4/80+ monocytes (inflamed plots; upper right quadrants) and latex+F4/80– neutrophils (inflamed plots; upper left quadrants) appearing in the peritoneum, since some neutrophils transiently carry latex in this labeling protocol (24). In the inflamed peritoneum, latex+Ly-6Chi monocytes outnumbered latex+ neutrophils 4:1, even though neutrophils dominate in acute peritoneal inflammation, in contrast to what occurs in atherosclerosis. (B) The graph shows the actual frequency of latex+ Ly-6Clo or Ly-6Chi monocytes in the inflamed peritoneum (gray bars), determined by flow cytometry, compared with the expected/known frequency (white bars) at which they would enter the peritoneum as unlabeled cells (“expected” data are derived from previously published calculations [ref. 16], as described in Methods). n = 4 mice per group. Differences between the actual and expected frequencies were not significant. (C) Levels of plasma cytokines (± SD) were measured at baseline or 2, 12, and 24 hours after administration of latex in the Ly-6Chi or Ly-6Clo monocyte labeling protocol. n = 3 mice per time point.