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

By F. Tacke, David Alvarez, Theodore J Kaplan, Claudia V. Jakubzick, R. Spanbroek, Jaime Llodrá, Alexandre Garin, Jianhua Liu, M. Mack, N. Van Rooijen and 3 more. Journal of Clinical Investigation, 2007

1,384 citations recorded by the source corpus.

Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2(+)CX3CR1(+)Ly-6C(hi) and CCR2(-)CX3CR1(++)Ly-6C(lo) monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X(3)-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-6C(hi) monocytes in apoE(-/-) mice fed a high-fat diet. CCR2(+)Ly-6C(hi) monocytes efficiently accumulated in plaques, whereas CCR2(-)Ly-6C(lo) 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-6C(hi) 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/a494840816eb463071f92fea18805f3e603e32ee

How researchers see this paper

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In Immunology

1. Peter Libby
2. I. Tabas
3. G. Hansson
4. A. Lichtman
5. P. Ridker
6. Christian Weber
7. A. Mildner
8. M. Guilliams

In Oncology

1. Peter Libby
2. Eric G. Pamer
3. F. Geissmann
4. A. Mildner
5. A. Lichtman
6. K. Woollard
7. G. Hansson
8. I. Tabas

Citations in the corpus

• Immune Effector Mechanisms Implicated in Atherosclerosis: From Mice to Humans (2013, background): “After initiating an atherogenic diet, the blood of hypercholesterolemic mice shows a dramatic increase in Ly6chi monocytes (Swirski et al., 2007) (Tacke et al., 2007).”
• Monocyte-Macrophages and T Cells in Atherosclerosis (2017, neutral): “and Garcı́a-Cardeña, 2013), promotes the entry into the intima of bone-marrow-derived monocytes (Tacke et al., 2007; Swirski et al., 2016).”
• Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. (2010, methodology): “To investigate this, we selectively labeled Ly6C or Ly6C monocyte subsets in vivo with fluorescent latex beads, using a previously described procedure (14, 15).”
• Obesity, inflammation, and atherosclerosis (2009, background): “Monocytes seem to commit to distinct roles while in the blood, and exhibit different recruitment mechanisms and functions in the plaque reflected by their surface structure”
• Monocyte recruitment during infection and inflammation (2011, background): “Recruitment of LY6C low monocytes is partially dependent on CCR5, which is upregulated in the LY6C low monocyte population in Apoe −/− mic”
• The Cellular Biology of Macrophages in Atherosclerosis (2011, positive): “A study in fat-fed Apoe knockout mice suggests that a population of DCs in atherosclerotic lesions originates from Ly-6C monocytes (Tacke et al., 2007).”
• Monocytes in atherosclerosis: subsets and functions (2010, background): “Little, however, is known about how the lack of apoE affects the Gr1 − /Ly6C low population, with the numbers remaining unaffected in some studie”
• History of Discovery: Inflammation in Atherosclerosis (2012, background): “Hypercholesterolemic mice have high levels of monocytes that exhibit particularly proinflammatory functions, delineated by high expression of the surface marker Ly6C, in the peripheral blood and spleen.(33,34) In severely hypercholesterolemic mice, extramedullary leukopoiesis in the spleen yields en”
• Progress and challenges in translating the biology of atherosclerosis (2011, background): “In mice, a pro-inflammatory subset of monocytes induced by hyperlipidaemia may preferentially furnish the precursors of lesional foam cells, but the fates and functions of this monocyte subset and its human equivalent remain under intense exploratio”
• Inflammation in Atherosclerosis: From Pathophysiology to Practice (2009, background): “(10,11) (12) Hyperlipidemia elicits a profound enrichment of a pro-inflammatory subset of monocytes in the mouse.”