Key Concepts:

Figure 1. Mechanisms involved in foam cell formation and development of the atherosclerotic lesion. (a) Microphotograph of the normal intima after oil red O staining. Very few oil red O-positive lipid infiltrations are detected in the normal intima (Were kindly provided by Andrew C Li, University of California, San Diego and is reproduced from Andrew C Li and Wulf Palinski (2006) Peroxisome proliferator-activated receptors: How their effects on macrophages can lead to the development of a new drug therapy against atherosclerosis. Annual Review of Pharmacology and Toxicology 46:1–39, with permission from Annual Reviews Inc.). (b) Microphotograph of the earliest stage of an atherosclerotic lesion, the fatty streak, after staining with oil red O. The fatty streak is characterised by subendothelial accumulation of macrophages/foam cells, which contain massive amounts of lipids, as indicated by oil red O staining (Were kindly provided by Andrew C Li, University of California, San Diego. From Elsevier.). (c) Atherogenesis is a chronic inflammatory process. Under conditions of hypercholesterolaemia, LDL accumulates in the arterial intima and is progressively oxidised by endothelial and other arterial cells. Endothelial cells also become activated, thus increasing the expression of adhesion molecules, including selectins, VCAM-1 and ICAM-1, on their surfaces. OxLDL and MCP-1 act as chemo-attractants for circulating monocytes which then attach to endothelial cells via adhesion molecules. CCR2, the receptor for MCP-1, is upregulated in circulating monocytes and further increases their rate of recruitment. Monocytes transmigrate to the subendothelial space, where they transform into macrophages and begin producing enzymes that oxidatively modify LDL, such as 12/15-LO and enzymes that produce ROS. Oxidised LDL is rapidly taken up by scavenger receptors, such as CD36 and SR-A. The rapid accumulation of cholesteryl esters results in foam cell formation. Infiltrated macrophages and foam cells also participate in the inflammatory process by secretion of pro-inflammatory cytokines, such as TNF, IL-1 and IL-6. Homeostatic responses to prevent accumulation of foam cells include upregulation of the expression of molecules that participate in cholesterol efflux to HDL, such as apoE and ABCA1. Original magnification of microphotographs is 40×. (c) is an adaptation from Glass and Witztum (2001) with permission from Elsevier.

Figure 2. Macrophage responses to PPAR and LXR activation. Macrophages have availability to free fatty acids (FFAs) via the action of fatty acid synthase (FAS) or phospholipase A2 (PLA2) or via LPL-mediated lipolysis of triglyceride-rich lipoproteins. Conversion of FFAs to eicosanoids, such as prostaglandins (PGs) and leukotriens (LTs), provides ligands for PPARs. The uptake of oxLDL by scavenger receptors (SRs), including CD36, provides oxysterols that can activate LXRs. Activated PPARs and LXRs upregulate the expression of target genes through heterodimerisation with RXR and binding to the response elements PPARE and LXRE, respectively. Both PPARs and LXRs induce the expression of genes involved in macrophage lipid homeostasis (in red). For example, PPARs upregulate the expression of genes involved in mitochondrial -oxidation, including Cpt1, Ech1 and Pex11a, and LXRs induce the expression of genes that participate in cholesterol efflux, such as ABCA1 and apoE. PPARs and LXRs also participate in modulation of innate and acquired immunity by transrepressing the expression of selective subsets of pro-inflammatory genes each (in blue). MIG, macrophage induced gene; iNOS, inducible nitric oxide synthase; MIP, macrophage inflammatory protein. An adaptation from Ricote et al. (2004).

Figure 3. Foam cell formation in the granuloma during the infection with Mycobacterium tuberculosis. (a) Bacilli that reside within macrophages overproduce lipids such as trehalose dimycolates (TDM) that consolidate as multivesicular bodies and are subsequently exocytosed to the extracellular milieu. Through the scavenger receptors (SRs) and Toll-like receptors (TLRs) the exocytosed bodies are internalised on macrophages which then become foam cells. (b) Cross-talk between macrophages and T_H1 lymphocytes.