Monocyte Mayhem

Abstract

Atherosclerosis is a lipoprotein disorder with inflammatory, vascular, and hemodynamic determinants. Total white blood cell count and subpopulations including granulocytes, monocytes, T cells, and bone marrow-derived precursors have been implicated in atherosclerotic cardiovascular disease (CVD).1,2 Although these associations may inform biological processes, they have not, to date, permitted specific mechanistic understanding of subsets of leukocytes involved nor have they advanced risk prediction and therapeutic targeting or monitoring in the clinic. Although short-lived in circulation, blood monocytes are proposed to play a specific role in atherosclerosis because (1) blood monocytes are the major source of tissue macrophages; (2) monocyte-derived macrophages and dendritic cells are the predominant leukocytes in atherosclerotic lesion; and (3) macrophages/dendritic cells have a variety of important proinflammatory (inflammatory recruitment/activation of other leukocytes and vascular cells, foam cell formation and lipid accumulation, fibrous cap erosion, and plaque rupture) and anti-inflammatory (phagocytosis, efferocytosis, and leukocyte egress) actions in experimental atherosclerotic lesions.1,3,4 Despite these mechanistic insights from human pathology and experimental studies in rodents, there have been disparate findings in studies of total monocyte counts and CVD.5,6 Article see p 122 There are several challenges to our understanding of the role of monocytes in atherosclerosis.7,8 First, circulating monocytes are heterogeneous due to subtype differentiation in bone marrow. The regulation and rate of subpopulation recruitment as well as their roles in atherosclerosis are uncertain. Second, monocyte subpopulations are typically defined by differential expression of specific cell surface antigens including receptors that modulate their function, for example, chemokine receptors chemokine (C-C motif) receptor 2 (CCR2), CX3C chemokine receptor 1 (CX3CR1), and C-C chemokine receptor type 5 (CCR5), as well as adhesion molecule integrin receptors very late antigen-4 (also called integrin α4β1) and LFA-1(integrin αLβ …