Inflammation as a Therapeutic Target in Atherosclerosis

Abstract

Atherosclerotic coronary artery disease (CAD) results from build-up of cholesterol-rich plaques in the walls of the coronary arteries and is a leading cause of death. Inflammation is central to atherosclerosis. Uncontrolled inflammation makes coronary plaques "unstable" and vulnerable to rupture or erosion, leading to thrombosis and myocardial infarction (MI). As multiple inflamed plaques often co-exist in the coronary system, patients are at risk of repeated atherothrombotic cardiovascular events after MI, with rates of 10-12% at one year and 18-20% at three years. This is largely because current therapies for CAD, such as lipid-lowering statins, do not adequately control plaque inflammation. New anti-atherosclerotic agents are therefore needed, especially those that better target inflammation. The recent positive results for the anti-interleukin-1-beta (IL-1β) monoclonal antibody, Canakinumab, in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) clinical trial has provided a major stimulant to the field. It highlights that not only is inflammation important from a pathogenic and risk prediction perspective in CAD, but that reducing inflammation can be beneficial. The challenge is now to find the best strategies to achieve this in real-world practice. This review outlines the role that inflammation plays in atherosclerosis and provides an update on anti-inflammatory therapies currently being investigated to target atherosclerosis.

Keywords: C-reactive protein; atherosclerosis; canakinumab; colchicine; inflammation; interleukin; methotrexate.

Figure 1

Infiltration of low-density lipoprotein (LDL) and formation of macrophage foam cells in the arterial wall. In individuals with hypercholesterolaemia, elevated levels of LDL-C are prone to infiltration and retention in the arterial wall. Monocytes recruited into the arterial wall differentiate into macrophages on stimulation by macrophage colony stimulating factor (M-CSF). Modified LDL particles are then taken up by macrophages via scavenger receptors. Accumulation of lipids in the macrophage results in the formation of lipid-laden foam cells leading to the release of pro-inflammatory cytokines. CD36, cluster of differentiation-36; ICAM, intercellular cell adhesion molecule 1; IL-1β, interleukin-1-beta; LDL-C, low-density lipoprotein cholesterol; M-CSF, macrophage colony stimulating factor; oxLDL, oxidised low density lipoproteins; TNF-α, tumor necrosis factor alpha; SR-A1, scavenger receptor type 1; VCAM-1, vascular cell adhesion molecule 1.

Figure 2

Inflammatory pathways involved in atherosclerosis. Data from preclinical and clinical trials suggest an intricate balance between pro-inflammatory and anti-inflammatory pathways. It is this balance that determines the development and progression of atherosclerotic plaque that may result in the thrombotic complications associated with plaque rupture. CRP, C-reactive protein; MMPs, matrix metalloproteinases; IFN-γ, interferon-gamma; IL-1α, interleukin-1-alpha; IL-1β, interleukin-1-beta; IL-2, interleukin-2; IL-6, interleukin-6; IL-10, interleukin-10; IL-18, interleukin-18; Lp-PLA₂, lipoprotein-associated phospholipase A2; TGF-β, transforming growth factor beta; Th-1, T-helper-1 lymphocyte; TNF-α, tumor necrosis factor alpha; T-reg, regulatory T lymphocyte.

Figure 3

Two signal activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Activation of the NLRP3 inflammasome requires both the initial priming step (left) following by the activation step (right). Priming of macrophages is provided by endogenous cytokines (IL-1 and TNF-α) and binding of PAMPs on microbial molecules to membrane-bound TLR. The second activation step involves a variety of stimuli, including intracellular oxLDL accumulation, PAMPs, and crystalloid particulates such as uric and cholesterol crystals. The NLRP3 inflammasome catalyses the conversion of pro-caspase-1 to its active form, caspase-1, which then converts pro-IL-1β and pro-IL-18 into their bioactive, pro-atherogenic forms, IL-1β and IL-18. ASC, apoptosis-associated speck-like protein; IL-1, interleukin 1; IL-1R, interleukin-1 receptor; NLRP3, NOD-like receptor family pyrin domain containing 3; oxLDL, oxidised low-density lipoproteins; PAMPs, pathogen-associated molecular patterns; ROS, reactive oxygen species; TLR, toll-like receptors; TNF-α, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptors.