Home LiteratureArticle Details
PMID: 21529710 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Macrophages in the pathogenesis of atherosclerosis.

Cell ·Vol. 145 ·No. 3 ·2011-04-29 ·Pages 341-55

Moore KJ, Tabas I

Abstract

In atherosclerosis, the accumulation of apolipoprotein B-lipoproteins in the matrix beneath the endothelial cell layer of blood vessels leads to the recruitment of monocytes, the cells of the immune system that give rise to macrophages and dendritic cells. Macrophages derived from these recruited monocytes participate in a maladaptive, nonresolving inflammatory response that expands the subendothelial layer due to the accumulation of cells, lipid, and matrix. Some lesions subsequently form a necrotic core, triggering acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death. This Review discusses the central roles of macrophages in each of these stages of disease pathogenesis.

MeSH Terms
Animals Atherosclerosis/immunology,metabolism Dendritic Cells/immunology Humans Macrophages/immunology,pathology Monocytes/pathology Signal Transduction
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Moore Kathryn J
Department of Medicine, New York University Medical Center, NY 10016, USA.
Tabas Ira
References (109)
109 references, click to expand
  1. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages.
    J Biol Chem. 2002 Dec 20;277(51):49982-8 PMID: 12376530
  2. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.
    Nature. 2010 Apr 29;464(7293):1357-61 PMID: 20428172
  3. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages.
    J Biol Chem. 2008 Aug 22;283(34):22930-41 PMID: 18552351
  4. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression.
    J Clin Invest. 2011 May;121(5):2025-36 PMID: 21505265
  5. Decreased atherosclerosis in low-density lipoprotein receptor knockout mice transplanted with Abcg1-/- bone marrow.
    Arterioscler Thromb Vasc Biol. 2006 Oct;26(10):2308-15 PMID: 16917103
  6. The cholesteryl ester cycle in macrophage foam cells. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters.
    J Biol Chem. 1980 Oct 10;255(19):9344-52 PMID: 7410428
  7. Lysosomal cysteine proteases in atherosclerosis.
    Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1359-66 PMID: 15178558
  8. The impact of macrophage insulin resistance on advanced atherosclerotic plaque progression.
    Circ Res. 2010 Jan 8;106(1):58-67 PMID: 20056946
  9. Role of polymorphonuclear neutrophils in atherosclerosis: current state and future perspectives.
    Atherosclerosis. 2010 May;210(1):1-13 PMID: 19931081
  10. High-density lipoprotein heterogeneity and function in reverse cholesterol transport.
    Curr Opin Lipidol. 2010 Jun;21(3):229-38 PMID: 20480549
  11. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice.
    Nat Med. 2009 Jan;15(1):97-103 PMID: 19122657
  12. Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity.
    Curr Opin Lipidol. 2004 Apr;15(2):167-74 PMID: 15017359
  13. Leukocytosis and ischemic vascular disease morbidity and mortality: is it time to intervene?
    Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):658-70 PMID: 15662026
  14. Spatiotemporal controlled delivery of nanoparticles to injured vasculature.
    Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2213-8 PMID: 20133865
  15. Granulocyte macrophage colony-stimulating factor regulates dendritic cell content of atherosclerotic lesions.
    Arterioscler Thromb Vasc Biol. 2007 Mar;27(3):621-7 PMID: 17158354
  16. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia.
    Circulation. 2008 Aug 5;118(6):672-7 PMID: 18678783
  17. Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice.
    Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):174-9 PMID: 15499039
  18. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.
    J Clin Invest. 1994 Dec;94(6):2493-503 PMID: 7989608
  19. Impaired development of atherosclerosis in Abcg1-/- Apoe-/- mice: identification of specific oxysterols that both accumulate in Abcg1-/- Apoe-/- tissues and induce apoptosis.
    Arterioscler Thromb Vasc Biol. 2010 Jun;30(6):1174-80 PMID: 20299684
  20. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.
    J Clin Invest. 1998 Feb 15;101(4):890-8 PMID: 9466984
  21. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.
    Nat Immunol. 2010 Feb;11(2):155-61 PMID: 20037584
  22. Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions.
    Cell Metab. 2010 Aug 4;12(2):142-53 PMID: 20674859
  23. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2.
    Circ Res. 2010 Sep 17;107(6):737-46 PMID: 20651288
  24. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR.
    Immunity. 2009 Aug 21;31(2):245-58 PMID: 19646905
  25. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches.
    J Am Coll Cardiol. 2008 Jun 10;51(23):2199-211 PMID: 18534265
  26. Oxidation, lipoproteins, and atherosclerosis: which is wrong, the antioxidants or the theory?
    Curr Opin Clin Nutr Metab Care. 2005 Mar;8(2):139-46 PMID: 15716791
  27. Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men.
    Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1050-9 PMID: 18323516
  28. Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis.
    Cell Metab. 2008 Dec;8(6):492-501 PMID: 19041765
  29. Apoptotic cell removal.
    Curr Biol. 2001 Oct 2;11(19):R795-805 PMID: 11591341
  30. Lipoprotein-associated phospholipase A(2) and atherosclerosis.
    Curr Opin Lipidol. 2009 Oct;20(5):415-20 PMID: 19667981
  31. Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet.
    Circ Res. 2009 Nov 20;105(11):1072-82 PMID: 19834009
  32. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease.
    Nat Genet. 2009 Mar;41(3):283-5 PMID: 19198611
  33. The response-to-retention hypothesis of early atherogenesis.
    Arterioscler Thromb Vasc Biol. 1995 May;15(5):551-61 PMID: 7749869
  34. Vulnerable plaque: the pathology of unstable coronary lesions.
    J Interv Cardiol. 2002 Dec;15(6):439-46 PMID: 12476646
  35. The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor.
    J Biol Chem. 2009 Nov 20;284(47):32336-43 PMID: 19783654
  36. Effect of gamma-irradiation and bone marrow transplantation on atherosclerosis in LDL receptor-deficient mice.
    Arterioscler Thromb Vasc Biol. 2001 Oct;21(10):1674-80 PMID: 11597944
  37. New observations on the trafficking and diapedesis of monocytes.
    Curr Opin Hematol. 2010 Jan;17(1):43-52 PMID: 19996887
  38. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation.
    PLoS One. 2010 Jul 23;5(7):e11765 PMID: 20668705
  39. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages.
    Nat Immunol. 2010 May;11(5):411-8 PMID: 20351694
  40. Site-specific effects of PECAM-1 on atherosclerosis in LDL receptor-deficient mice.
    Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):1996-2002 PMID: 18669884
  41. A macrophage sterol-responsive network linked to atherogenesis.
    Cell Metab. 2010 Feb 3;11(2):125-35 PMID: 20142100
  42. Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association.
    Circulation. 2010 Feb 23;121(7):948-54 PMID: 20177011
  43. ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2.
    J Lipid Res. 2008 Jan;49(1):169-82 PMID: 17916878
  44. Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways.
    J Clin Invest. 2009 Oct;119(10):2925-41 PMID: 19741297
  45. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions.
    Cell Metab. 2006 Apr;3(4):257-66 PMID: 16581003
  46. A role for the apoptosis inhibitory factor AIM/Spalpha/Api6 in atherosclerosis development.
    Cell Metab. 2005 Mar;1(3):201-13 PMID: 16054063
  47. Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis.
    Cell Metab. 2008 Nov;8(5):372-83 PMID: 19046569
  48. The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques.
    Circ Res. 2000 Feb 4;86(2):131-8 PMID: 10666407
  49. Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation.
    Nature. 2009 Apr 30;458(7242):1180-4 PMID: 19407801
  50. Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice.
    J Clin Invest. 2005 Aug;115(8):2192-201 PMID: 16075060
  51. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP.
    Cell Metab. 2009 May;9(5):474-81 PMID: 19416717
  52. Catheter-based adenovirus-mediated anti-monocyte chemoattractant gene therapy attenuates in-stent neointima formation in cynomolgus monkeys.
    Atherosclerosis. 2007 Oct;194(2):309-16 PMID: 17126840
  53. A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma.
    J Lipid Res. 2008 Oct;49(10):2230-9 PMID: 18594118
  54. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis.
    Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1256-61 PMID: 15831805
  55. Genome-wide association studies in atherothrombosis.
    Eur J Intern Med. 2010 Apr;21(2):74-8 PMID: 20206874
  56. Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein.
    J Biol Chem. 2005 Jan 21;280(3):2352-60 PMID: 15533943
  57. ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis.
    Circ Res. 2010 Jun 25;106(12):1861-9 PMID: 20431058
  58. Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice.
    Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):2003-8 PMID: 18688018
  59. Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation.
    Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):787-95 PMID: 20150557
  60. Lipoprotein(a) enhances advanced atherosclerosis and vascular calcification in WHHL transgenic rabbits expressing human apolipoprotein(a).
    J Biol Chem. 2002 Dec 6;277(49):47486-92 PMID: 12196525
  61. Atherosclerosis. the road ahead.
    Cell. 2001 Feb 23;104(4):503-16 PMID: 11239408
  62. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome.
    Circulation. 2007 Sep 11;116(11):1226-33 PMID: 17709641
  63. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.
    Cell. 1997 May 2;89(3):331-40 PMID: 9150132
  64. Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes.
    Circ Res. 2009 Mar 27;104(6):e42-54 PMID: 19265038
  65. Macrophage death and defective inflammation resolution in atherosclerosis.
    Nat Rev Immunol. 2010 Jan;10(1):36-46 PMID: 19960040
  66. Genetically programmed biases in Th1 and Th2 immune responses modulate atherogenesis.
    Am J Pathol. 2008 Jun;172(6):1500-8 PMID: 18467709
  67. Advanced atherosclerotic foam cell formation has features of an acquired lysosomal storage disorder.
    Rejuvenation Res. 2006 Summer;9(2):245-55 PMID: 16706652
  68. Matrix metalloproteinase-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques.
    Circulation. 2005 Oct 25;112(17):2708-15 PMID: 16230484
  69. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice.
    J Clin Invest. 2006 Jan;116(1):59-69 PMID: 16374516
  70. Inflammation in atherosclerosis: visualizing matrix metalloproteinase action in macrophages in vivo.
    Circulation. 2006 Jul 4;114(1):55-62 PMID: 16801460
  71. Macrophage heterogeneity in atherosclerotic plaques.
    Curr Opin Lipidol. 2009 Oct;20(5):370-8 PMID: 19741337
  72. Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice.
    J Clin Invest. 2007 Dec;117(12):3900-8 PMID: 17992262
  73. Mouse models of atherosclerosis.
    Science. 1996 May 3;272(5262):685-8 PMID: 8614828
  74. Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogenic lipoproteins with smooth muscle cells and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein(a) retention and macrophage foam cell formation.
    J Biol Chem. 1993 Sep 25;268(27):20419-32 PMID: 8376399
  75. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis.
    Cell Metab. 2008 May;7(5):365-75 PMID: 18460328
  76. Monocyte-endothelial cell interactions in the development of atherosclerosis.
    Trends Cardiovasc Med. 2008 Aug;18(6):228-32 PMID: 19185814
  77. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice.
    J Clin Invest. 2003 Oct;112(8):1176-85 PMID: 14561702
  78. LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression.
    J Clin Invest. 2010 Dec;120(12):4415-24 PMID: 21041949
  79. Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile.
    J Exp Med. 2010 Feb 15;207(2):391-404 PMID: 20100871
  80. Cholesterol sensing, trafficking, and esterification.
    Annu Rev Cell Dev Biol. 2006;22:129-57 PMID: 16753029
  81. Regulation of macrophage function in inflammation and atherosclerosis.
    J Lipid Res. 2009 Apr;50 Suppl:S277-81 PMID: 18987388
  82. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis.
    Circ Res. 2010 Feb 5;106(2):383-90 PMID: 19893012
  83. Modulation of atherosclerosis in mice by Toll-like receptor 2.
    J Clin Invest. 2005 Nov;115(11):3149-56 PMID: 16211093
  84. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.
    J Clin Invest. 2007 Jan;117(1):185-94 PMID: 17200718
  85. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.
    Nat Rev Immunol. 2008 May;8(5):349-61 PMID: 18437155
  86. Matrix-metalloproteinase-14 deficiency in bone-marrow-derived cells promotes collagen accumulation in mouse atherosclerotic plaques.
    Circulation. 2008 Feb 19;117(7):931-9 PMID: 18250269
  87. Safety of anacetrapib in patients with or at high risk for coronary heart disease.
    N Engl J Med. 2010 Dec 16;363(25):2406-15 PMID: 21082868
  88. The problem of passenger genes in transgenic mice.
    Arterioscler Thromb Vasc Biol. 2007 Oct;27(10):2100-3 PMID: 17690316
  89. The oxidative modification hypothesis of atherosclerosis: does it hold for humans?
    Trends Cardiovasc Med. 2001 Apr-May;11(3-4):93-102 PMID: 11686009
  90. Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice.
    Arterioscler Thromb Vasc Biol. 2009 Jan;29(1):19-26 PMID: 18948635
  91. Monocyte-derived dendritic cells.
    Semin Immunol. 2005 Aug;17(4):313-8 PMID: 15955712
  92. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice.
    FASEB J. 2010 Aug;24(8):2869-80 PMID: 20354139
  93. Induction of ER stress in macrophages of tuberculosis granulomas.
    PLoS One. 2010 Sep 15;5(9):e12772 PMID: 20856677
  94. PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance.
    Nat Med. 2009 Nov;15(11):1266-72 PMID: 19838202
  95. Dendritic cells in atherosclerosis: current status of the problem and clinical relevance.
    Eur Heart J. 2005 Sep;26(17):1700-4 PMID: 15855191
  96. Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms.
    Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1553-8 PMID: 12869351
  97. The role of endoplasmic reticulum stress in the progression of atherosclerosis.
    Circ Res. 2010 Oct 1;107(7):839-50 PMID: 20884885
  98. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation.
    Science. 2010 Jun 25;328(5986):1689-93 PMID: 20488992
  99. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis.
    J Exp Med. 2007 May 14;204(5):1057-69 PMID: 17485518
  100. Animal models of spontaneous plaque rupture: the holy grail of experimental atherosclerosis research.
    Curr Atheroscler Rep. 2002 May;4(3):238-42 PMID: 11931722
  101. The endoplasmic reticulum stress-C/EBP homologous protein pathway-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques.
    Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1925-32 PMID: 20651282
  102. The pathogenesis of atherosclerosis--an update.
    N Engl J Med. 1986 Feb 20;314(8):488-500 PMID: 3511384
  103. Imaging atherosclerosis and vulnerable plaque.
    J Nucl Med. 2010 May 1;51 Suppl 1:51S-65S PMID: 20395341
  104. A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation.
    Blood. 2007 Feb 1;109(3):1026-33 PMID: 17047157
  105. Emerging role of Toll-like receptors in atherosclerosis.
    J Lipid Res. 2009 Apr;50 Suppl:S340-5 PMID: 18980945
  106. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves.
    J Exp Med. 2009 Mar 16;206(3):497-505 PMID: 19221394
  107. Role of cholesterol and lipid organization in disease.
    Nature. 2005 Dec 1;438(7068):612-21 PMID: 16319881
  108. Liver x receptor signaling pathways and atherosclerosis.
    Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1513-8 PMID: 20631351
  109. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress.
    Cell Metab. 2010 Nov 3;12(5):467-82 PMID: 21035758
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2011.04.005
Published
2011-04-29
Pages
341-55
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3111065
Subset
IM
Grants
NIA NIH HHS · R01-AG20255 · United States
NHLBI NIH HHS · R01 HL075662-08 · United States
NHLBI NIH HHS · R01 HL057560 · United States
NHLBI NIH HHS · R01 HL075662 · United States
NHLBI NIH HHS · R01 HL106019 · United States
NHLBI NIH HHS · R01 HL106019-02 · United States
NHLBI NIH HHS · P01-HL087123 · United States
NHLBI NIH HHS · R01-HL057560 · United States
NHLBI NIH HHS · P01-HL054591 · United States
NHLBI NIH HHS · P01 HL054591 · United States
NHLBI NIH HHS · P01 HL087123-05 · United States
NHLBI NIH HHS · R01-HL075662 · United States
NIA NIH HHS · R01 AG020255-09 · United States
NHLBI NIH HHS · P01 HL087123 · United States
NIA NIH HHS · R01 AG020255 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2011.04.005 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2