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-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.

Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis

“…Injured muscle only recruits CX3CR1 lo /Ly-6C + MOs/MPs that subsequently switch into antiinfl ammatory CX3CR1 hi / Ly-6C − MOs/MPs and differentiate into MPs We labeled each circulating subset with fl uorescent latex beads (LXs) before injury, as previously described (12,15). Labeling of MOs does not alter their migratory capacities (12).…”

Monocytes and Macrophages in Cancer: Development and Functions

“…A major role in mobilization and recruitment of Ly6C high monocytes, under both homeostatic and pathological conditions, has been attributed to the chemokine receptor CCR2 (CD192), bound by the chemokines CCL2 and CCL7 [32][33][34]. CCL2 (monocyte chemotactic protein-1 or MCP-1) is expressed by many nucleated cell types in response to pro-inflammatory or microbial stimuli and the role of the CCL2-CCR2-axis in recruitment of Ly6C high monocytes to sites of inflammation has been demonstrated for various pathological conditions (such as infection, atherosclerosis and diabetes) [32][33][34][35][36]. In cancer, CCL2 was identified as the first tumor-derived factor (TDF) that induced chemotaxis in monocytes [37].…”

Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation

“…15,23,[44][45][46][47][48][49][50] Under those conditions, CX 3 CL1 may facilitate the adhesion and transmigration of Mos. 51 Additionally, it has been recently proposed that a direct and evolutionary conserved role for CX 3 CR1-CX 3 CL1 interactions is involved in Mo survival. 43 Although chemokines were originally defined as chemoattractants, a growing body of evidence indicates their additional involvement in the control of cell survival.…”