Review Article | Published:

The macrophage foam cell as a target for therapeutic intervention


Specialized functions of macrophages have evolved to protect the body from infection. However, the same mechanisms that enable phagocytosis of pathogens and activation of leukocytes also permit the uptake of lipoproteins and release of reactive oxygen species and immune mediators that collectively contribute to atherosclerosis. New approaches to inhibit lipid accumulation in macrophage foam cells and reduce inflammatory responses may be of therapeutic value in preventing coronary artery disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: Critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675–680 (2001).

  2. 2

    Gough, P.J. & Gordon, S. The role of scavenger receptors in the innate immune system. Microbes Infect. 2, 305–311 (2000).

  3. 3

    Gordon, S., Clarke, S., Greaves, D. & Doyle, A. Molecular immunobiology of macrophages: recent progress. Curr. Opin. Immunol. 7, 24–33 (1995).

  4. 4

    Libby, P., Ridker, P.M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).

  5. 5

    Glass, C. & Witztum, J. Atherosclerosis. the road ahead. Cell 104, 503–516 (2001).

  6. 6

    Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med 340, 115–126 (1999).

  7. 7

    Smith, J.D. et al. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulting factor (op) and apolipoprotein E. Proc. Natl. Acad. Sci. USA 92, 8264–8268 (1995).

  8. 8

    Linton, M.F. & Fazio, S. Class A scavenger receptors, macrophages, and atherosclerosis. Curr. Opin. Lipidol. 12, 489–495 (2001).

  9. 9

    de Villiers, W.J. & Smart, E.J. Macrophage scavenger receptors and foam cell formation. J. Leukoc. Biol. 66, 740–746 (1999).

  10. 10

    Hansson, G.K. Immune mechanisms in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 21, 1876–1890 (2001).

  11. 11

    Glagov, S., Weisenberg, E., Zarins, C.K., Stankunavicius, R. & Kolettis, G.J. Compensatory enlargement of human atherosclerotic coronary arteries. N. Engl. J. Med. 316, 1371–1375 (1987).

  12. 12

    Davies, M.J., Richardson, P.D. & Woolf, N. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br. Heart J. 69, 377–381 (1993).

  13. 13

    Dansky, H.M. et al. Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage. Arterioscler. Thromb. Vasc. Biol. 21, 1662–1667 (2001).

  14. 14

    Cybulsky, M.I. & Gimbrone, M.A., Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251, 788–791 (1991).

  15. 15

    Cybulsky, M.I. et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J. Clin. Invest. 107, 1255–1262 (2001).

  16. 16

    Collins, R.G. et al. P-selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J. Exp. Med. 191, 189–194 (2000).

  17. 17

    Boring, L., Gosling, J., Cleary, M. & Charo, I.F. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394, 894–897 (1998).

  18. 18

    Gu, L. et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein-deficient mice. Mol. Cell 2, 275–281 (1998).

  19. 19

    Gosling, J. et al. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J. Clin. Invest. 103, 773–778 (1999).

  20. 20

    Han, K.H., Han, K.O., Green, S.R. & Quehenberger, O. Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased in hypercholesterolemia. Differential effects of plasma lipoproteins on monocyte function. J. Lipid Res. 40, 1053–1063 (1999).

  21. 21

    Boisvert, W., Santiago, R., Curtiss, L. & Terkeltaub, R. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J. Clin. Invest. 101, 353–363 (1998).

  22. 22

    Cushing, S.D. et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl. Acad. Sci. USA 87, 5134–5130 (1990).

  23. 23

    Subbanagounder, G. et al. Epoxyisoprostane and epoxycyclopentenone phospholipids regulate monocyte chemotactic protein-1 and interleukin-8 synthesis. Formation of these oxidized phospholipids in response to interleukin-1β. J. Biol. Chem. 277, 7271–7281 (2002).

  24. 24

    Ni, W. et al. New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice. Circulation 103, 2096–2101 (2001).

  25. 25

    Skalen, K. et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417, 750–754 (2002).

  26. 26

    Steinberg, D. & Witztum, J.L. Lipoproteins, Lipoprotein, Oxidation, and Atherogenesis 458–475 (W.B. Saunders Co., Philadelphia, 1999).

  27. 27

    Gaut, J.P. & Heinecke, J.W. Mechanisms for oxidizing low-density lipoprotein. Insights from patterns of oxidation products in the artery wall and from mouse models of atherosclerosis. Trends Cardiovasc. Med. 11, 103–112 (2001).

  28. 28

    Babior, B.M. Phagocytes and oxidative stress. Am. J. Med. 109, 33–44 (2000).

  29. 29

    Mehrabian, M. et al. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ. Res. 91, 120–126 (2002).

  30. 30

    Cyrus, T. et al. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J. Clin. Invest. 103, 1597–1604 (1999).

  31. 31

    Harats, D. et al. Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arteriosler. Thromb. Vasc. Biol. 20, 2100–2105 (2000).

  32. 32

    Sendobry, S.M. et al. Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties. Br. J. Pharmacol. 120, 1199–1206 (1997).

  33. 33

    Bocan, T.M. et al. A specific 15-lipoxygenase inhibitor limits the progression and monocyte-macrophage enrichment of hypercholesterolemia-induced atherosclerosis in the rabbit. Atherosclerosis 136, 203–216 (1998).

  34. 34

    Shen, J. et al. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J. Clin. Invest. 98, 2201–2208 (1996).

  35. 35

    Detmers, P.A. et al. Deficiency in inducible nitric oxide synthase results in reduced atherosclerosis in apolipoprotein E-deficient mice. J. Immunol. 165, 3430–3435 (2000).

  36. 36

    Shi, W. et al. Paradoxical reduction of fatty streak formation in mice lacking endothelial nitric oxide synthase. Circulation 105, 2078–2082 (2002).

  37. 37

    Niu, X.L. et al. Inducible nitric oxide synthase deficiency does not affect the susceptibility of mice to atherosclerosis but increases collagen content in lesions. Circulation 103, 1115–1120 (2001).

  38. 38

    Ihrig, M., Dangler, C.A. & Fox, J.G. Mice lacking inducible nitric oxide synthase develop spontaneous hypercholesterolaemia and aortic atheromas. Atherosclerosis 156, 103–107 (2001).

  39. 39

    Daugherty, A., Dunn, J.L., Rateri, D.L. & Heinecke, J.W. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J. Clin. Invest. 94, 437–444 (1994).

  40. 40

    Brennan, M.L. et al. Increased atherosclerosis in myeloperoxidase-deficient mice. J Clin Invest 107, 419–430 (2001).

  41. 41

    Steinberg, D. & Witztum, J.L. Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis? Circulation 105, 2107–2111 (2002).

  42. 42

    Scheidegger, K.J., Butler, S. & Witztum, J.L. Angiotensin II increases macrophage-mediated modification of low density lipoprotein via a lipoxygenase-dependent pathway. J. Biol. Chem. 272, 21609–21615 (1997).

  43. 43

    Hayek, T. et al. The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice. Cardiovasc. Res. 44, 579–587 (1999).

  44. 44

    Boullier, A. et al. Scavenger receptors, oxidized LDL, and atherosclerosis. Ann. NY Acad. Sci. 947, 214–222 (2001).

  45. 45

    Febbraio, M., Hajjar, D.P. & Silverstein, R.L. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J. Clin. Invest. 108, 785–791 (2001).

  46. 46

    Shaw, P. et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J. Clin. Invest. 105, 1731–1740 (2000).

  47. 47

    Acton, S. et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271, 518–520 (1996).

  48. 48

    Ji, Y. et al. Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile. J. Biol. Chem. 274, 33398–33402 (1999).

  49. 49

    Kozarsky, K.F. et al. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature 387, 414–417 (1997).

  50. 50

    Krieger, M. Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems. J. Clin. Invest. 108, 793–797 (2001).

  51. 51

    Braun, A. et al. Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice. Circ. Res. 90, 270–276 (2002).

  52. 52

    Huszar, D. et al. Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1. Arterioscler. Thromb. Vasc. Biol. 20, 1068–1073 (2000).

  53. 53

    Chen, W., Silver, D.L., Smith, J.D. & Tall, A.R. Scavenger receptor-BI inhibits ATP-binding cassette transporter 1-mediated cholesterol efflux in macrophages. J. Biol. Chem. 275, 30794–30800 (2000).

  54. 54

    Brewer, H.B., Jr. The lipid-laden foam cell: An elusive target for therapeutic intervention. J. Clin. Invest. 105, 703–705 (2000).

  55. 55

    Accad, M. et al. Massive zanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1. J. Clin. Invest. 105, 711–719 (2000).

  56. 56

    Fazio, S. et al. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. J. Clin. Invest. 107, 163–171 (2001).

  57. 57

    Escary, J.L. et al. Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages. J. Lipid Res. 40, 397–404 (1999).

  58. 58

    Kusunoki, J. et al. Acyl-CoA:cholesterol acyltransferase inhibition reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 103, 2604–2609 (2001).

  59. 59

    Brown, M.S. & Goldstein, J.L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc. Natl. Acad. Sci. USA 96, 11041–11048 (1999).

  60. 60

    Chawla, A., Repa, J., Evans, R. & Mangelsdorf, D. Nuclear receptors and lipid physiology: Opening the X-Files. Science 294, 1866–1870 (2001).

  61. 61

    Laffitte, B.A. et al. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl. Acad. Sci. USA 98, 507–512 (2001).

  62. 62

    Repa, J.J. et al. Regulation of mouse sterol regulatory element-binding protein-1c (SREBP-1c) by oxysterol receptors LXR-α and LXR-β. Genes Dev. 14, 2819–2830 (2000).

  63. 63

    Chawla, A. et al. A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell 7, 161–171 (2001).

  64. 64

    Tall, A.R. & Wang, N. Tangier disease as a test of the reverse cholesterol transport hypothesis. J. Clin. Invest. 106, 1205–1207 (2000).

  65. 65

    Aiello, R.J. et al. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler. Thromb. Vasc. Biol. 22, 630–637 (2002).

  66. 66

    van Eck, M. et al. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues. Proc. Natl. Acad. Sci. USA 99, 6298–6303 (2002).

  67. 67

    Singaraja, R.R. et al. Increased ABCA1 activity protects against atherosclerosis. J. Clin. Invest. 110, 35–42 (2002).

  68. 68

    Clee, S.M. et al. Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease. Circulation 103, 1198–1205 (2001).

  69. 69

    Claudel, T. et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. Proc. Natl. Acad. Sci. USA 98, 2610–2615 (2001).

  70. 70

    Joseph, S.B. et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl. Acad. Sci. USA 99, 7604–7609 (2002).

  71. 71

    Goldberg, I.J. & Merkel, M. Lipoprotein lipase: physiology, biochemistry, and molecular biology. Front. Biosci. 6, D388–405 (2001).

  72. 72

    Mead, J.R. & Ramji, D.P. The pivotal role of lipoprotein lipase in atherosclerosis. Cardiovasc. Res. 55, 261–269 (2002).

  73. 73

    Yagyu, H. et al. Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice. J. Lipid Res. 40, 1677–1685 (1999).

  74. 74

    Wilson, K., Fry, G.L., Chappell, D.A., Sigmund, C.D. & Medh, J.D. Macrophage-specific expression of human lipoprotein lipase accelerates atherosclerosis in transgenic apolipoprotein e knockout mice but not in C57BL/6 mice. Arterioscler. Thromb. Vasc. Biol. 21, 1809–1815 (2001).

  75. 75

    Babaev, V.R. et al. Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivo. J. Clin. Invest. 103, 1697–1705 (1999).

  76. 76

    Wang, Y. & Oram, J.F. Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1. J. Biol. Chem. 277, 5692–5697 (2002).

  77. 77

    Barbier, O. et al. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 22, 717–726 (2002).

  78. 78

    Oliver, W.R., Jr. et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc. Natl. Acad. Sci. USA 98, 5306–5311 (2001).

  79. 79

    Daugherty, A. et al. The effects of total lymphocyte deficiency on the extent of atherosclerosis in apolipoprotein E−/− mice. J. Clin. Invest. 100, 1575–1580 (1997).

  80. 80

    Song, L., Leung, C. & Schindler, C. Lymphocytes are important in early atherosclerosis. J. Clin. Invest. 108, 251–259 (2001).

  81. 81

    Reardon, C.A. et al. Effect of immune deficiency on lipoproteins and atherosclerosis in male apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 21, 1011–1016 (2001).

  82. 82

    Dansky, H.M., Charlton, S.A., Harper, M.M. & Smith, J.D. T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. Proc. Natl. Acad. Sci. USA 94, 4662–4646 (1997).

  83. 83

    Horkko, S. et al. Immunological responses to oxidized LDL. Free Radic. Biol. Med. 28, 1771–1779 (2000).

  84. 84

    Panousis, C.G. & Zuckerman, S.H. Interferon-γ induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler. Thromb. Vasc. Biol. 20, 1565–1571 (2000).

  85. 85

    Gupta, S. et al. IFN-γ potentiates atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 2752–2761 (1997).

  86. 86

    Pinderski, L.J. et al. Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient mice by altering lymphocyte and macrophage phenotypes. Circ. Res. 90, 1064–1071 (2002).

  87. 87

    Mallat, Z. et al. Protective role of interleukin-10 in atherosclerosis. Circ. Res. 85, e17–24 (1999).

  88. 88

    Palinski, W. & Tsimikas, S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis. J. Am. Soc. Nephrol. 13, 1673–1681 (2002).

  89. 89

    Yasojima, K., Schwab, C., McGeer, E.G. & McGeer, P.L. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am. J. Pathol. 158, 1039–1051 (2001).

  90. 90

    Willson, T.M., Lambert, M.H. & Kliewer, S.A. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu. Rev. Biochem. 70, 341–367 (2001).

  91. 91

    Klappacher, G.W. & Glass, C.K. Roles of peroxisome proliferator-activated receptor gamma in lipid homeostasis and inflammatory responses of macrophages. Curr. Opin. Lipidol. 13, 305–312 (2002).

  92. 92

    Haffner, S.M. et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 106, 679–684 (2002).

  93. 93

    Burleigh, M.E. et al. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation 105, 1816–1823 (2002).

Download references


Because of space limitations, we were unable to cite all of the primary sources of data discussed in this review. We thank J.L. Witztum for comments and A. Zulueta for assistance with preparation of the manuscript. We thank the Stanford University Donald W. Reynolds Center and National Institutes of Health grants to the La Jolla Specialized Center for Research on Molecular Medicine and Atherosclerosis for support.

Author information

Correspondence to Christopher K. Glass.

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

  • Issue Date


Further reading

Figure 1: Photomicrograph of a macrophage foam cell isolated from a hypercholesterolemic mouse.
Figure 2: Mechanisms contributing to the recruitment of monocytes to the artery wall and their differentiation into macrophages.

D. Maizels

Figure 3: Mechanisms contributing to foam-cell formation.

D. Maizels

Figure 4: Mechanisms that act to protect cells from toxic effects of free cholesterol.

D. Maizels

Figure 5: Interactions of macrophages with Th1 and Th2 cells that influence the development of atherosclerosis.

D. Maizels