A proposed mechanism for atherosclerosis development and the roles of PON1 and PON2 against atherosclerosis. Moving from left to right, low-density lipoprotein (LDL) diffuses from the blood into the innermost layer of the artery. The LDL in the artery wall is modified by oxygen radicals to oxidized LDL (oxLDL) which in turn induces endothelial cells to express leukocyte adhesion molecules, such as vascular cell-adhesion molecule-1 (VCAM1), intercellular adhesion molecule-1 (ICAM-1), and P-selectins. Monocytes and T cells bind to adhesion molecules-expressing endothelial cells and respond to locally produced chemokines by migrating into the arterial tissue. Monocytes differentiate into macrophages in response to local macrophage colony-stimulating factor (M-CSF) and other stimuli. Scavenger receptors mediate macrophage uptake of ox-LDL particles, which leads to intracellular cholesterol accumulation and the formation of foam cells. Ox-LDL and other ligands promote the production of many pro-inflammatory molecules by macrophages. T cells undergo activation after interacting with antigen-presenting cells (APCs), such as macrophages or dendritic cells. A T helper 1 (TH1)-cell-dominated response ensues, possibly owing to the local production of interleukin-12 (IL-12), IL-18 and other cytokines. TH1 cells produce inflammatory cytokines including interferon-α (IFN-α) and tumour-necrosis factor (TNF). These cytokines and others prompt macrophage activation, production of other pro-inflammatory mediators, activate endothelial cells, increase adhesion-molecule expression and the propensity for thrombus formation, and stimulate proliferation and migration of smooth-muscle-cell as well as collagen production. Plaque inflammation might be attenuated in response to the anti-inflammatory cytokines IL-10 and transforming growth factor-α (TGF-α), which are produced by several cell types including regulatory T and TH2cells, macrophages, and for TGF-α, also vascular cells and platelets. The atherosclerotic lesion has a core of lipids, including cholesterol crystals, living and apoptotic cells and a fibrous cap with smooth muscle cells and collagen. Several types of cells of the immune response are present throughout the atheroma including macrophages, T cells, mast cells and DCs. HDL-associated PON1 inhibits the influx of cholesterol by oxidized LDL into macrophages by reducing Ox-LDL levels, reducing Ox-LDL uptake via the macrophage scavenger receptor, reducing macrophage-mediated oxidation of LDL, and increasing the hydrolysis of macrophage oxidized lipids. HDL-associated PON1 also inhibits macrophage cholesterol biosynthesis and enhances HDL-mediated cholesterol efflux. Monocyte/macrophage-associated PON2 also protects LDL against oxidation and reduces the oxidative stress caused by preformed ox-LDL. TCR; T-cell receptor, TLR; Toll-like receptor, MCH; Major histocompatibility complex, ROS; Reactive oxygen species.