Inflammation in atherosclerosis: from pathophysiology to practice

Abstract

Until recently, most envisaged atherosclerosis as a bland arterial collection of cholesterol, complicated by smooth muscle cell accumulation. According to that concept, endothelial denuding injury led to platelet aggregation and release of platelet factors which would trigger the proliferation of smooth muscle cells in the arterial intima. These cells would then elaborate an extracellular matrix that would entrap lipoproteins, forming the nidus of the atherosclerotic plaque. Beyond the vascular smooth muscle cells long recognized in atherosclerotic lesions, subsequent investigations identified immune cells and mediators at work in atheromata, implicating inflammation in this disease. Multiple independent pathways of evidence now pinpoint inflammation as a key regulatory process that links multiple risk factors for atherosclerosis and its complications with altered arterial biology. Knowledge has burgeoned regarding the operation of both innate and adaptive arms of immunity in atherogenesis, their interplay, and the balance of stimulatory and inhibitory pathways that regulate their participation in atheroma formation and complication. This revolution in our thinking about the pathophysiology of atherosclerosis has now begun to provide clinical insight and practical tools that may aid patient management. This review provides an update of the role of inflammation in atherogenesis and highlights how translation of these advances in basic science promises to change clinical practice.

Figures

Figure 1. Elements involved in innate immunity

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 pro-inflammatory 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-1 (IL–1). The less inflammatory subset of monocytes express higher levels of transforming growth factor beta (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 – 8/14 (MRP-8/14), platelet-derived growth factor (PDGF), and TGF-beta.

Figure 2. Cells involved in atherosclerosis express pattern recognition receptors involved in innate immunity

With the cooperation of CD14, TLR4 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.

Figure 3. Cells involved in adaptive immunity

The text describes the functional roles of the five classes of lymphocytes depicted in atherosclerosis. B cells elaborate antibodies (Ab). A specialized subset of B cells (B1 cells) elaborate primarily IgM antibodies, including natural antibodies that recognize constituents of oxidized LDL (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. IFN-γ—interferon-gamma; TNF—tumor necrosis factor; IL-4— interleukin-4; TGF-β—transforming growth factor beta; IL-10—interleukin-10; hsp60—heat shock protein 60. 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. (66,67)

Figure 4. Cumulative incidence of cardiovascular events in the JUPITER trial, according to study group

Panel A shows the cumulative incidence of the primary endpoint (nonfatal myocardial infarction, nonfatal stroke, arterial revascularization, hospitalization for unstable angina, or confirmed death from a cardiovascular cause). Panel B shows the cumulative incidence of nonfatal myocardial infarction, nonfatal stroke, or confirmed death from a cardiovascular cause. Panel C shows cumulative incidence for arterial revascularization or hospitalization for unstable angina. Panel D shows the cumulative incidence of death from any cause. [Adopted from Ridker PM, Danielson E, Fonseca FAH, Genest J, Gottto AM, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.]

Figure 5. Effects of rosuvastatin on the primary trial endpoint, according to baseline characteristics of the JUPITER cohort

[Adopted from Ridker PM, Danielson E, Fonseca FAH, Genest J, Gottto AM, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.]

Figure 6. Hazard ratios for incident cardiovascular events in the JUPITER trial according to achieved concentrations of LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) after initiation of rosuvastatin therapy

Data were adjusted for age, baseline LDL and HDL cholesterol, baseline hsCRP, blood pressure, gender, body mass index, smoking status, and parental history of premature coronary heart disease. Event rates are per 100 person-years. [Adopted from Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, on behalf of the JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009;373:1175-1182.]