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Thromb Haemost 2011; 106(05): 763-771
DOI: 10.1160/TH11-05-0320
Theme Issue Article
Schattauer GmbH

Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation

Ine M. J. Wolfs
1   Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
,
Marjo M. P. C. Donners
1   Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
,
Menno P. J. de Winther
1   Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
› Author Affiliations Financial support: The work in the group of Dr. de Winther is funded by the Netherlands Heart Foundation (grants 2007T067 and 2010B022) and the Netherlands Organization for Scientific Research (Vidi 016–066–329). Dr. Donners is also supported by the Netherlands Heart Foundation (grant 2007T034). Dr de Winther is an established investigator of the Netherlands Heart Foundation.
Further Information

Publication History

Received: 11 May 2011

Accepted after minor revision: 23 August 2011

Publication Date:
23 November 2017 (online)

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Summary

The phenotype of macrophages in atherosclerotic lesions can vary dramatically, from a large lipid laden foam cell to a small inflammatory cell. Classically, the concept of macrophage heterogeneity discriminates between two extremes called either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Polarisation of plaque macrophages is predominantly determined by the local micro-environment present in the atherosclerotic lesion and is rather more complex than typically described by the M1/M2 paradigm. In this review we will discuss the role of various polarising factors in regulating the phenotypical state of plaque macrophages. We will focus on two main levels of phenotype regulation, one determined by differentiation factors produced in the lesion and the other determined by T-cell-derived polarising cytokines. With foam cell formation being a key characteristic of macrophages during atherosclerosis initiation and progression, these polarisation factors will also be linked to lipid handling of macrophages.

Keywords

Macrophage heterogeneity - polarisation - atherosclerosis - cytokines - micro-environment
 

  • References

  • 1 Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8: 958-969.
    CrossrefPubMedSearch in Google Scholar
  • 2 Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity 2010; 32: 593-604.
    CrossrefPubMedSearch in Google Scholar
  • 3 Martinez FO, Sica A, Mantovani A. et al. Macrophage activation and polarization. Front Biosci 2008; 13: 453-461.
    CrossrefPubMedSearch in Google Scholar
  • 4 Krausgruber T, Blazek K, Smallie T. et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol 2011; 12: 231-238.
    CrossrefPubMedSearch in Google Scholar
  • 5 El Chartouni C, Schwarzfischer L, Rehli M. Interleukin-4 induced interferon regulatory factor (Irf) 4 participates in the regulation of alternative macrophage priming. Immunobiology 2010; 215: 821-825.
    CrossrefPubMedSearch in Google Scholar
  • 6 Sinha P, Clements VK, Ostrand-Rosenberg S. Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol 2005; 174: 636-645.
    CrossrefPubMedSearch in Google Scholar
  • 7 Porta C, Rimoldi M, Raes G. et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci USA 2009; 106: 14978-14983.
    CrossrefPubMedSearch in Google Scholar
  • 8 Bouhlel MA, Derudas B, Rigamonti E. et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 2007; 6: 137-143.
    CrossrefPubMedSearch in Google Scholar
  • 9 Sica A, Larghi P, Mancino A. et al. Macrophage polarization in tumour progression. Semin Cancer Biol 2008; 18: 349-355.
    CrossrefPubMedSearch in Google Scholar
  • 10 Tidball JG, Villalta SA. Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 2010; 298: R1173-1187.
    CrossrefPubMedSearch in Google Scholar
  • 11 Lee S, Huen S, Nishio H. et al. Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol 2011; 22: 317-326.
    CrossrefPubMedSearch in Google Scholar
  • 12 Kadl A, Meher AK, Sharma PR. et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res 2010; 107: 737-746.
    CrossrefPubMedSearch in Google Scholar
  • 13 Gleissner CA, Shaked I, Little KM. et al. CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J Immunol 2010; 184: 4810-4818.
    CrossrefPubMedSearch in Google Scholar
  • 14 Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003; 19: 71-82.
    CrossrefPubMedSearch in Google Scholar
  • 15 Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 2009; 27: 669-692.
    CrossrefPubMedSearch in Google Scholar
  • 16 Swirski FK, Libby P, Aikawa E. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007; 117: 195-205.
    CrossrefPubMedSearch in Google Scholar
  • 17 Tacke F, Alvarez D, Kaplan TJ. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007; 117: 185-194.
    CrossrefPubMedSearch in Google Scholar
  • 18 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
    CrossrefPubMedSearch in Google Scholar
  • 19 Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 2008; 8: 802-815.
    CrossrefPubMedSearch in Google Scholar
  • 20 Gijbels MJ, van der Cammen M, van der Laan LJ. et al. Progression and regression of atherosclerosis in APOE3-Leiden transgenic mice: an immunohistochemical study. Atherosclerosis 1999; 143: 15-25.
    CrossrefPubMedSearch in Google Scholar
  • 21 Poston RN, Hussain IF. The immunohistochemical heterogeneity of atheroma macrophages: comparison with lymphoid tissues suggests that recently blood-derived macrophages can be distinguished from longer-resident cells. J Histochem Cytochem 1993; 41: 1503-1512.
    CrossrefPubMedSearch in Google Scholar
  • 22 Stoger JL, Goossens P, de Winther MP. Macrophage heterogeneity: relevance and functional implications in atherosclerosis. Curr Vasc Pharmacol 2010; 8: 233-248.
    CrossrefPubMedSearch in Google Scholar
  • 23 van der Wal AC, Das PK, Bentz van de Berg D. et al. Atherosclerotic lesions in humans. In situ immunophenotypic analysis suggesting an immune mediated response. Lab Invest 1989; 61: 166-170.
    PubMedSearch in Google Scholar
  • 24 Chinetti-Gbaguidi G, Baron M, Bouhlel MA. et al. Human Atherosclerotic Plaque Alternative Macrophages Display Low Cholesterol Handling but High Phagocytosis Because of Distinct Activities of the PPAR{gamma} and LXRα Pathways. Circ Res 2011; 108: 985-995.
    CrossrefPubMedSearch in Google Scholar
  • 25 Komohara Y, Hirahara J, Horikawa T. et al. AM-3K, an anti-macrophage antibody, recognizes CD163, a molecule associated with an anti-inflammatory macrophage phenotype. J Histochem Cytochem 2006; 54: 763-771.
    CrossrefPubMedSearch in Google Scholar
  • 26 Buechler C, Ritter M, Orso E. et al. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 2000; 67: 97-103.
    CrossrefPubMedSearch in Google Scholar
  • 27 Boyle JJ, Harrington HA, Piper E. et al. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 2009; 174: 1097-1108.
    CrossrefPubMedSearch in Google Scholar
  • 28 Sindrilaru A, Peters T, Wieschalka S. et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest 2011; 121: 985-997.
    CrossrefPubMedSearch in Google Scholar
  • 29 Khallou-Laschet J, Varthaman A, Fornasa G. et al. Macrophage plasticity in experimental atherosclerosis. PLoS One 2010; 5: e8852
    CrossrefPubMedSearch in Google Scholar
  • 30 Feig JE, Parathath S, Rong JX. et al. Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques. Circulation 2011; 123: 989-998.
    CrossrefPubMedSearch in Google Scholar
  • 31 Loke P, Gallagher I, Nair MG. et al. Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection. J Immunol 2007; 179: 3926-3936.
    CrossrefPubMedSearch in Google Scholar
  • 32 Hiasa M, Abe M, Nakano A. et al. GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF-alpha converting enzyme (TACE). Blood 2009; 114: 4517-4526.
    CrossrefPubMedSearch in Google Scholar
  • 33 Verreck FA, de Boer T, Langenberg DM. et al. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci USA 2004; 101: 4560-4565.
    CrossrefPubMedSearch in Google Scholar
  • 34 Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008; 8: 533-544.
    CrossrefPubMedSearch in Google Scholar
  • 35 Brocheriou I, Maouche S, Durand H. et al. Antagonistic regulation of macrophage phenotype by M-CSF and GM-CSF: implication in atherosclerosis. Atherosclerosis 2011; 214: 316-324.
    CrossrefPubMedSearch in Google Scholar
  • 36 Fleetwood AJ, Lawrence T, Hamilton JA. et al. Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol 2007; 178: 5245-5252.
    CrossrefPubMedSearch in Google Scholar
  • 37 van Tits LJ, Stienstra R, van Lent PL. et al. Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: a crucial role for Kruppel-like factor 2. Atherosclerosis 2011; 214: 345-349.
    CrossrefPubMedSearch in Google Scholar
  • 38 Waldo SW, Li Y, Buono C. et al. Heterogeneity of human macrophages in culture and in atherosclerotic plaques. Am J Pathol 2008; 172: 1112-1126.
    CrossrefPubMedSearch in Google Scholar
  • 39 Sierra-Filardi E, Vega MA, Sanchez-Mateos P. et al. Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release. Immunobiology 2010; 215: 788-795.
    CrossrefPubMedSearch in Google Scholar
  • 40 Xu W, Schlagwein N, Roos A. et al. Human peritoneal macrophages show functional characteristics of M-CSF-driven anti-inflammatory type 2 macrophages. Eur J Immunol 2007; 37: 1594-1599.
    CrossrefPubMedSearch in Google Scholar
  • 41 Filonzi EL, Zoellner H, Stanton H. et al. Cytokine regulation of granulocyte-macrophage colony stimulating factor and macrophage colony-stimulating factor production in human arterial smooth muscle cells. Atherosclerosis 1993; 99: 241-252.
    CrossrefPubMedSearch in Google Scholar
  • 42 Sakai M, Biwa T, Matsumura T. et al. Glucocorticoid inhibits oxidized LDL-induced macrophage growth by suppressing the expression of granulocyte/macrophage colony-stimulating factor. Arterioscler Thromb Vasc Biol 1999; 19: 1726-1733.
    CrossrefPubMedSearch in Google Scholar
  • 43 Liao F, Berliner JA, Mehrabian M. et al. Minimally modified low density lipoprotein is biologically active in vivo in mice. J Clin Invest 1991; 87: 2253-2257.
    CrossrefPubMedSearch in Google Scholar
  • 44 Plenz G, Koenig C, Severs NJ. et al. Smooth muscle cells express granulocyte-macrophage colony-stimulating factor in the undiseased and atherosclerotic human coronary artery. Arterioscler Thromb Vasc Biol 1997; 17: 2489-2499.
    CrossrefPubMedSearch in Google Scholar
  • 45 Frostegard J, Ulfgren AK, Nyberg P. et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 1999; 145: 33-43.
    CrossrefPubMedSearch in Google Scholar
  • 46 Kazawa T, Kawasaki T, Sakamoto A. et al. Expression of liver X receptor alpha and lipid metabolism in granulocyte-macrophage colony-stimulating factor-induced human monocyte-derived macrophage. Pathol Int 2009; 59: 152-160.
    CrossrefPubMedSearch in Google Scholar
  • 47 Irvine KM, Andrews MR, Fernandez-Rojo MA. et al. Colony-stimulating factor-1 (CSF-1) delivers a proatherogenic signal to human macrophages. J Leukoc Biol 2009; 85: 278-288.
    CrossrefPubMedSearch in Google Scholar
  • 48 Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 1989; 135: 169-175.
    PubMedSearch in Google Scholar
  • 49 de Boer OJ, van der Wal AC, Verhagen CE. et al. Cytokine secretion profiles of cloned T cells from human aortic atherosclerotic plaques. J Pathol 1999; 188: 174-179.
    CrossrefPubMedSearch in Google Scholar
  • 50 Geng YJ, Holm J, Nygren S. et al. Expression of the macrophage scavenger receptor in atheroma. Relationship to immune activation and the T-cell cytokine interferon-gamma. Arterioscler Thromb Vasc Biol 1995; 15: 1995-2002.
    CrossrefPubMedSearch in Google Scholar
  • 51 Uyemura K, Demer LL, Castle SC. et al. Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest 1996; 97: 2130-2138.
    CrossrefPubMedSearch in Google Scholar
  • 52 Mallat Z, Heymes C, Ohan J. et al. Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. Arterioscler Thromb Vasc Biol 1999; 19: 611-616.
    CrossrefPubMedSearch in Google Scholar
  • 53 Kleemann R, Zadelaar S, Kooistra T. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 2008; 79: 360-376.
    CrossrefPubMedSearch in Google Scholar
  • 54 Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006; 86: 515-581.
    CrossrefPubMedSearch in Google Scholar
  • 55 King VL, Cassis LA, Daugherty A. Interleukin-4 does not influence development of hypercholesterolemia or angiotensin II-induced atherosclerotic lesions in mice. Am J Pathol 2007; 171: 2040-2047.
    CrossrefPubMedSearch in Google Scholar
  • 56 Zhou X, Paulsson G, Stemme S. et al. Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apo E-knockout mice. J Clin Invest 1998; 101: 1717-1725.
    CrossrefPubMedSearch in Google Scholar
  • 57 Davenport P, Tipping PG. The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol 2003; 163: 1117-1125.
    CrossrefPubMedSearch in Google Scholar
  • 58 Pinderski LJ, Fischbein MP, Subbanagounder G. 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 2002; 90: 1064-1071.
    CrossrefPubMedSearch in Google Scholar
  • 59 Nakagawa T, Nozaki S, Nishida M. et al. Oxidized LDL increases and interferon-gamma decreases expression of CD36 in human monocyte-derived macrophages. Arterioscler Thromb Vasc Biol 1998; 18: 1350-1357.
    CrossrefPubMedSearch in Google Scholar
  • 60 Panousis CG, Zuckerman SH. Regulation of cholesterol distribution in macrophage-derived foam cells by interferon-gamma. J Lipid Res 2000; 41: 75-83.
    PubMedSearch in Google Scholar
  • 61 Geng YJ, Hansson GK. Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages. J Clin Invest 1992; 89: 1322-1330.
    CrossrefPubMedSearch in Google Scholar
  • 62 Wang XQ, Panousis CG, Alfaro ML. et al. Interferon-gamma-mediated downregulation of cholesterol efflux and ABC1 expression is by the Stat1 pathway. Arterioscler Thromb Vasc Biol 2002; 22: e5-9.
    CrossrefPubMedSearch in Google Scholar
  • 63 Panousis CG, Zuckerman SH. Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler Thromb Vasc Biol 2000; 20: 1565-1571.
    CrossrefPubMedSearch in Google Scholar
  • 64 Brand K, Mackman N, Curtiss LK. Interferon-gamma inhibits macrophage apolipoprotein E production by posttranslational mechanisms. J Clin Invest 1993; 91: 2031-2039.
    CrossrefPubMedSearch in Google Scholar
  • 65 Reiss AB, Awadallah NW, Malhotra S. et al. Immune complexes and IFN-gamma decrease cholesterol 27-hydroxylase in human arterial endothelium and macrophages. J Lipid Res 2001; 42: 1913-1922.
    PubMedSearch in Google Scholar
  • 66 Feng J, Han J, Pearce SF. et al. Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma. J Lipid Res 2000; 41: 688-696.
    PubMedSearch in Google Scholar
  • 67 Cornicelli JA, Butteiger D, Rateri DL. et al. Interleukin-4 augments acetylated LDL-induced cholesterol esterification in macrophages. J Lipid Res 2000; 41: 376-383.
    PubMedSearch in Google Scholar
  • 68 Halvorsen B, Waehre T, Scholz H. et al. Interleukin-10 enhances the oxidized LDL-induced foam cell formation of macrophages by antiapoptotic mechanisms. J Lipid Res 2005; 46: 211-219.
    CrossrefPubMedSearch in Google Scholar
  • 69 Han X, Kitamoto S, Lian Q. et al. Interleukin-10 facilitates both cholesterol uptake and efflux in macrophages. J Biol Chem 2009; 284: 32950-32958.
    CrossrefPubMedSearch in Google Scholar
  • 70 Han X, Kitamoto S, Wang H. et al. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice. FASEB J 2010; 24: 2869-2880.
    CrossrefPubMedSearch in Google Scholar
  • 71 Rubic T, Lorenz RL. Downregulated CD36 and oxLDL uptake and stimulated ABCA1/G1 and cholesterol efflux as anti-atherosclerotic mechanisms of interleukin-10. Cardiovasc Res 2006; 69: 527-535.
    CrossrefPubMedSearch in Google Scholar
  • 72 Lin J, Li M, Wang Z. et al. The role of CD4+CD25+ regulatory T cells in macrophage-derived foam-cell formation. J Lipid Res 2010; 51: 1208-1217.
    CrossrefPubMedSearch in Google Scholar