Macrophage Foam Cells

Abstract

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 (2001) © 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. (2004). © 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.
close

References

A‐González N and Castrillo A (2011) Liver X receptors as regulators of macrophage inflammatory and metabolic pathways. Biochimica et Biophysica Acta 1812: 982–994.

Akiyama TE, Sakai S, Lambert G, et al. (2002) Conditional disruption of the peroxisome proliferator‐activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. Molecular and Cellular Biology 22: 2607–2619.

Amézaga N, Sanjurjo L, Julve J, et al. (2014) Human scavenger protein AIM increases foam cell formation and CD36‐mediated oxLDL uptake. Journal of Leukocyte Biology 95: 509–520.

Arai S, Shelton JM, Chen M, et al. (2005) A role for the apoptosis inhibitory factor AIM/Spα/Api6 in atherosclerosis development. Cell Metabolism 1: 201–213.

Arnold L, Henry A, Poron F, et al. (2007) Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. Journal of Experimental Medicine 204: 1057–1069.

Beaumont C and Delaby C (2009) Recycling iron in normal and pathological states. Seminars in Hematology 46: 328–338.

Bouhlel MA, Staels B and Chinetti‐Gbaguidi G (2008) Peroxisome proliferator‐activated receptors – from active regulators of macrophage biology to pharmacological targets in the treatment of cardiovascular disease. Journal of Internal Medicine 263: 28–42.

Brown MS and Goldstein JL (1986) A receptor‐mediated pathway for cholesterol homeostasis. Science 232: 34–47.

Castrillo A, Joseph SB, Vaidya SA, et al. (2003) Crosstalk between LXR and toll‐like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Molecular Cell 12: 805–816.

Chawla A, Boisvert WA, Lee CH, et al. (2001) A PPAR gamma‐LXR‐ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Molecular Cell 7: 161–171.

Chinetti G, Lestavel S, Bocher V, et al. (2001) PPAR‐alpha and PPAR‐gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nature Medicine 7: 53–58.

Cipollone F, Cicolini G and Bucci M (2008) Cyclooxygenase and prostaglandin synthases in atherosclerosis: recent insights and future perspectives. Pharmacology & Therapeutics 118: 161–180.

Flannagan RS, Cosio G and Grinstein S (2009) Antimicrobial mechanisms of phagocytes and bacterial evasion strategies. Nature Reviews. Microbiology 7: 355–366.

Fojo SS and Brewer HB (1992) Hypertriglyceridaemia due to genetic defects in lipoprotein lipase and apolipoprotein C‐II. Journal of Internal Medicine 231: 669–677.

Galkina E and Ley K (2007) Vascular adhesion molecules in atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 27: 2292–2301.

Gautier EL, Jakubzick C and Randolph GJ (2009) Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 29: 1412–1418.

Geissmann F, Jung S and Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19: 71–82.

Geissmann F, Manz MG, Jung S, et al. (2010) Development of monocytes, macrophages, and dendritic cells. Science 327: 656–661.

Ghisletti S, Huang W, Ogawa S, et al. (2007) Parallel SUMOylation‐dependent pathways mediate gene‐ and signal‐specific transrepression by LXRs and PPARgamma. Molecular Cell 25: 57–70.

Ginhoux F and Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nature Reviews in Immunology 14: 392–404.

Glass CK and Witztum J (2001) Atherosclerosis: the road ahead. Cell 104: 503–516.

Haffner SM, Greenberg AS, Weston WM, et al. (2002) Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 106: 679–684.

Hazen SL (2008) Oxidized phospholipids as endogenous pattern recognition ligands in innate immunity. Journal of Biological Chemistry 283: 15527–15531.

Hong C, Duit S, Jalonen P, et al. (2010) The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2. Journal of Biological Chemistry 285: 19720–19726.

Hume DA (2008) Macrophages as APC and the dendritic cell myth. Journal of Immunology 181: 5829–5835.

Li AC and Palinski W (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.

Lloberas J and Celada A (2009) p21(waf1/CIP1), a CDK inhibitor and a negative feedback system that controls macrophage activation. European Journal of Immunology 39: 691–694.

Mak PA, Laffitte BA, Desrumaux C, et al. (2002) Regulated expression of the apolipoprotein E/C‐I/C‐IV/C‐II gene cluster in murine and human macrophages. A critical role for nuclear liver X receptors alpha and beta. Journal of Biological Chemistry 277: 31900–31908.

Mantovani A, Garlanda C and Locati M (2009) Macrophage diversity and polarization in atherosclerosis: a question of balance. Arteriosclerosis, Thrombosis, and Vascular Biology 29: 1419–1423.

Mayerl C, Lukasser M, Sedivy R, et al. (2006) Atherosclerosis research from past to present‐‐on the track of two pathologists with opposing views, Carl von Rokitansky and Rudolf Virchow. Virchows Archiv 449: 96–103.

Menendez‐Gutierrez MP, Roszer T and Ricote M (2012) Biology and therapeutic applications of peroxisome proliferator‐ activated receptors. Current Topics in Medicinal Chemistry 12: 548–584.

Moore GB, Pickavance LC, Briscoe CP, et al. (2008) Energy restriction enhances therapeutic efficacy of the PPARgamma agonist, rosiglitazone, through regulation of visceral fat gene expression. Diabetes, Obesity & Metabolism 10: 251–263.

Noels H, Bernhagen J and Weber C (2009) Macrophage migration inhibitory factor: a noncanonical chemokine important in atherosclerosis. Trends in Cardiovascular Medicine 19: 76–86.

Paidassi H, Tacnet‐Delorme P, Arlaud GJ and Frachet P (2009) How phagocytes track down and respond to apoptotic cells. Critical Reviews in Immunology 29: 111–130.

Pandey AK and Sassetti CM (2008) Mycobacterial persistence requires the utilization of host cholesterol. Proceedings of the National Academy of Sciences of the United States of America 105: 4376–4380.

Pascual‐García M, Rué L, León T, et al. (2013) Reciprocal negative cross‐talk between liver X receptors (LXRs) and STAT1: effects on IFN‐γ‐induced inflammatory responses and LXR‐dependent gene expression. Journal of Immunology 190: 6520–6532.

Peyron P, Vaubourgeix J, Poquet Y, et al. (2008) Foamy macrophages from tuberculous patients' granulomas constitute a nutrient‐rich reservoir for M. tuberculosis persistence. PLoS Pathogens 4: e1000204.

Portugal LR, Fernandes LR, Pietra Pedroso VS, et al. (2008) Influence of low‐density lipoprotein (LDL) receptor on lipid composition, inflammation and parasitism during Toxoplasma gondii infection. Microbes and Infection 10: 276–284.

Repa JJ, Liang G, Ou J, et al. (2000) Regulation of mouse sterol regulatory element‐binding protein‐1c gene (SREBP‐1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes & Development 14: 2819–2830.

Repa JJ and Mangelsdorf DJ (2000) The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annual Review of Cell and Developmental Biology 16: 459–481.

Rhoades E, Hsu F, Torrelles JB, et al. (2003) Identification and macrophage‐activating activity of glycolipids released from intracellular Mycobacterium bovis BCG. Molecular Microbiology 48: 875–888.

Ricote M, Valledor AF and Glass CK (2004) Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 24: 230–239.

Saha P, Modarai B, Humphries J, et al. (2009) The monocyte/macrophage as a therapeutic target in atherosclerosis. Current Opinion in Pharmacology 9: 109–118.

Tabas I (2002) Consequences of cellular cholesterol accumulation: basic concepts and physiological implications. Journal of Clinical Investigation 110: 905–911.

Takahashi K, Kimura Y, Nagata K, et al. (2005) ABC proteins: key molecules for lipid homeostasis. Medical Molecular Morphology 38: 2–12.

Tangirala RK, Bischoff ED, Joseph SB, et al. (2002) Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proceedings of the National Academy of Sciences United States of America 99: 11896–11901.

Wagner BL, Valledor AF, Shao G, et al. (2003) Promoter‐specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression. Molecular and Cellular Biology 23: 5780–5789.

Welch JS, Ricote M, Akiyama TE, Gonzalez FJ and Glass CK (2003) PPARgamma and PPARdelta negatively regulate specific subsets of lipopolysaccharide and IFN‐gamma target genes in macrophages. Proceedings of the National Academy of Sciences United States of America 100: 6712–6717.

Yona S and Jung S (2010) LXRMonocytes: subsets, origins, fates and functions. Current Opinion in Hematology 17: 53–59.

Zelcer N, Hong C, Boyadjian R and Tontonoz P (2009) LXR regulates cholesterol uptake through Idol‐dependent ubiquitination of the LDL receptor. Science 325: 100–104.

Further Reading

Chinetti‐Gbaguidi G and Staels B (2009) Lipid ligand‐activated transcription factors regulating lipid storage and release in human macrophages. Biochimica et Biophysica Acta 1791: 486–493.

Galkina E and Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis. Annual Review of Immunology 27: 165–197.

Greaves DR and Gordon S (2009) The macrophage scavenger receptor at 30 years of age: current knowledge and future challenges. Journal of Lipid Research 50 (Suppl): S282–S286.

Korbel DS, Schneider BE and Schaible UE (2008) Innate immunity in tuberculosis: myths and truth. Microbes and Infection 10: 995–1004.

McLaren JE and Ramji DP (2009) Interferon gamma: a master regulator of atherosclerosis. Cytokine and Growth Factor Reviews 20: 125–135.

Russell DG, Cardona PJ, Kim MJ, et al. (2009) Foamy macrophages and the progression of the human tuberculosis granuloma. Nature Immunology 10: 943–948.

Silverstein RL (2009) Inflammation, atherosclerosis, and arterial thrombosis: role of the scavenger receptor CD36. Cleveland Clinic Journal of Medicine 76 (Suppl 2): S27–S30.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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