Macrophage Foam Cells


Foam cells are lipid‐loaded macrophages that are generated from the massive uptake of modified low‐density lipoproteins and the intracytoplasmatic accumulation of cholesteryl esters. Foam cells are present in all stages of atherosclerosis and participate in inflammatory responses and tissue remodelling within the arterial intima. Foam cells can also be generated as a consequence of infection by persistent pathogens, such as Mycobacterium, Chlamydia and Toxoplasma. These pathogens meet nutritional advantages by residing within cells that accumulate lipids. When the immune system is unable to eliminate substances perceived as foreign, it produces a granuloma, composed mostly of macrophages, attempting to wall off the non‐self material. This article reviews the processes that lead to the regulation of foam cell formation in atherosclerosis and infection.

Key Concepts

  • Foam cells are lipid‐loaded macrophages.
  • Foam cells are generated upon massive uptake of modified low‐density lipoproteins and the intracellular accumulation of cholesteryl esters.
  • Foam cells form during development of atherosclerosis and as a result of different infections.
  • Foam cells participate in inflammatory responses and tissue remodelling.
  • Endothelial transmigration of monocytes is the first step in the development of atherosclerosis.
  • Once monocytes reach the arterial wall intima, they undergo phenotypic transformation into macrophages, internalise large amounts of modified LDLs and become foam cells.
  • Heterodimers of liver X receptors (LXR) and retinoid X receptors (RXR) directly upregulate the expression of several genes involved in lipid and lipoprotein homeostasis.
  • When the immune system is unable to eliminate substances perceived as foreign, it produces a granuloma, composed mostly of macrophages, that attempts to wall off the non‐self material.

Keywords: foam cells; granuloma; low‐density lipoproteins; liver X receptors (LXRs); macrophages; nuclear receptors; peroxisome proliferator‐activated receptors (PPARs); retinoid X receptors (RXR); tuberculosis

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. (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. (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 chemoattractants for circulating monocytes that 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‐α, IL‐1β 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×. (a) and (b) were donated by Andrew C. Li (University of California, San Diego). Reproduced with permission from Glass and Witztum () © Cell Press.
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 leucotriens (LTs), provides ligands for PPARs. On the other hand, the uptake of oxLDL by 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 β‐oxidation, including Cpt1, Ech1 and PexIIa, 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. Adapted from Ricote et al. (). © American Heart Association.
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 multi‐vesicular bodies and are subsequently exocytosed to the extracellular milieu. Through the SRs and TLRs exocytosed bodies are taken up by macrophages that then become foam cells. (b) Cross‐talk between macrophages and TH1 lymphocytes.


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Further Reading

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Valledor, Annabel F, Lloberas, Jorge, and Celada, Antonio(Feb 2015) Macrophage Foam Cells. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020730.pub2]