This figure summarizes some of the functions ascribed to various cellular participants in atherosclerosis that may participate in the disease and its complication when dysregulated. Mononuclear phagocytes represent the bulwark of the innate immune defenses in mammals. Monocytes give rise to macrophages, which in the arterial intima form foam cells, the hallmark of the arterial fatty streak. Recent work has focused on heterogeneity of mononuclear phagocytes. We now recognize a proinflammatory subset distinct from a less inflammatory population of monocytes. The inflammatory subset expresses high levels of the cell-surface marker Ly6C (also known as GR-1) in the mouse. These inflammatory monocytes express higher levels of Toll-like receptors (TLR), and the other functions indicated, including elaboration of high levels of the cytokines tumor necrosis factor (TNF) and interleukin (IL)-1. The less inflammatory subset of monocytes express higher levels of transforming growth factor (TGF)-beta, the scavenger receptors CD36 and scavenger receptor A (SR-A), and angiogenic mediators including vascular endothelial growth factor (VEGF). Dendritic cells express human leukocyte antigen (HLA) molecules among the other indicated structures. Dendritic cells present antigens to T cells, linking innate to adaptive immunity. Mast cells elaborate many mediators as shown. Recent data support a causal role for mast cells in mouse atherosclerosis. Platelets also participate in adaptive immunity. When activated, platelets exteriorize CD40 ligand (CD40L or CD154) and release mediators including RANTES (regulated and T-cell expressed secreted), myeloid related protein (MRP)-8/14, platelet-derived growth factor (PDGF), and TGF-beta.

With the cooperation of CD14, Toll-like receptor (TLR) 4 binds bacterial lipopolysaccharides (LPS) and a variety of other potential instigators of inflammation and atherosclerosis including heat shock proteins (hsp). TLR2 usually exists as a heterodimer with TLR1 or TLR6. TLR2 complexes can bind microbial products as shown and, in addition, apolipoprotein CIII (Apo CIII). Scavenger receptor A binds modified low-density lipoproteins (LDL). CD36 binds oxidatively modified LDL. The receptor for advanced glycation endproducts (RAGE) also decorates many cells involved in atherosclerosis and may function in inflammatory signaling.

The text describes the functional roles of the 5 classes of lymphocytes depicted in atherosclerosis. B cells elaborate antibodies (Ab). A specialized subset of B cells (B1 cells) elaborate primarily immunoglobulin M antibodies, including natural antibodies that recognize constituents of oxidized low-density lipoprotein (oxLDL). The bottom panel of this figure portrays diagrammatically the effect of the various cell types on lesions, based mostly on experiments in mice. Up arrows indicate aggravation of lesion formation. Down arrows indicate reduction in lesion formation. This diagram summarizes the "net" effect attributed to the cell type on atherosclerosis primarily on the basis of experiments in mice. In some cases, this figure necessarily oversimplifies the complexity of the data. For example, not all TH₂ cell functions and not all antibodies elaborated by B cells may mitigate atherogenesis. CTL = cytolytic T lymphocytes; IFN = interferon; hsp = heat shock protein; Th = T helper cells; T_Reg = regulatory T cells; other abbreviations as in Figure 1.

A shows the cumulative incidence of the primary end point (nonfatal myocardial infarction, nonfatal stroke, arterial revascularization, hospitalization for unstable angina, or confirmed death from a cardiovascular cause). B shows the cumulative incidence of nonfatal myocardial infarction, nonfatal stroke, or confirmed death from a cardiovascular cause. C shows cumulative incidence for arterial revascularization or hospitalization for unstable angina. D shows the cumulative incidence of death from any cause.

Adapted, with permission, from Ridker et al. (53).

Adapted, with permission, from Ridker et al. (53). ATP = Adult Treatment Panel; BMI = body mass index; CHD = coronary heart disease; HX = history.

Data were adjusted for age, baseline low-density lipoprotein (LDL) and high-density lipoprotein cholesterol, baseline high-sensitivity C-reactive protein (hsCRP), blood pressure, sex, body mass index, smoking status, and parental history of premature coronary heart disease. Event rates are per 100 person-years. p < 0.001.

Adapted, with permission, from Ridker et al. (55).