Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis

Abstract

Monocytes are central mediators in the advance of atherosclerotic plaque, making them a natural therapeutic target for reducing disease burden. Here, we highlight recent advances in our current understanding of monocyte heterogeneity and its relevance to regulation of monocyte accumulation and function within atherosclerotic plaques. Differences that distinguish monocyte subsets include differential expression of chemokine receptors, especially CCR2 and CX3CR1. Ablation of expression of these 2 receptors (or their ligands) in mice has an additive inhibition on monocyte recruitment to atherosclerotic plaques. Moreover, simultaneously interfering with 3 key pathways--CCR2, CX3CR1, and CCR5--essentially abolishes atherosclerosis in mice. Here, we discuss how these chemokine receptors act at multiple points on at least 1 monocyte subset, regulating their mobilization from bone marrow, survival, or recruitment to plaques. Finally, we discuss how this knowledge may be useful clinically, emphasizing that CX3CR1 may in particular be a viable target for therapeutic manipulation of monocyte-derived cell fate in cardiovascular disease.

Figure 1

Cartoon depicting the major markers and frequency (relative %) of the two major monocyte subsets in human (top) and mouse (bottom) blood.

Figure 2

Cartoon depicts the life cycle of monocyte subsets and their recruitment to atherosclerotic plaques, with an emphasis on the role of chemokine receptors in these processes. Classical monocytes leave the bone marrow in a CCR2-dependent manner , . It remains unknown whether the development of nonclassical monocytes requires incubation in the bone marrow and mobilization into the bloodstream thereafter. In the bloodstream, the chemokine receptor CX3CR1 regulates the survival of nonclassical monocytes selectively, , , whereas the cytokine M-CSF, also a critical factor in atherosclerotic plaque development, controls survival of monocytes generally . Chemokine receptors CCR2, CX3CR1, and CCR5 are differentially involved in monocyte subset recruitment into plaques . Once in plaques, the persistence of monocyte-derived cells stemming from either subset appears to be regulated by CX3CR1 and it may also control their retention .