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Thromb Haemost 2011; 106(05): 772-778
DOI: 10.1160/TH11-05-0296
Theme Issue Article
Schattauer GmbH

Dendritic cells in atherosclerosis: Functions in immune regulation and beyond

Helga D. Manthey
Rudolf-Virchow-Center/ DFG-Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany
,
Alma Zernecke
Rudolf-Virchow-Center/ DFG-Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany
› Author Affiliations Financial support: This work was supported by the Deutsche Forschungsgemeinschaft (FOR809, ZE 827/1–2; SFB 688 TPA12; ZE 827/4–1).
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Publication History

Received: 03 May 2011

Accepted after minor revision: 02 August 2011

Publication Date:
23 November 2017 (online)

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Summary

Chronic inflammation drives the development of atherosclerosis. Dendritic cells (DCs) are known as central mediators of adaptive immune responses and the development of immunological memory and tolerance. DCs are present in non-diseased arteries, and accumulate within atherosclerotic lesions where they can be localised in close vicinity to T cells. Recent work has revealed important functions of DCs in regulating immune mechanisms in atherogenesis, and vaccination strategies using DCs have been explored for treatment of disease. However, in line with a phenotypical and functional overlap with plaque macrophages vascular DCs were also identified to engulf lipids, thus contributing to lipid burden in the vessel wall and initiation of lesion growth. Furthermore, a function of DCs in regulating cholesterol homeostasis has been revealed. Finally, phenotypically distinct plasmacytoid dendritic cells (pDCs) have been identified within atherosclerotic lesions. This review will dissect the multifaceted contribution of DCs and pDCs to the initiation and progression of atherosclerosis and the experimental approaches utilising DCs in therapeutic vaccination strategies.

Keywords

Atherosclerosis - inflammation - dendritic cells
 

  • References

  • 1 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340: 115-126.
    CrossrefPubMedGoogle Scholar
  • 2 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
    CrossrefPubMedGoogle Scholar
  • 3 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
    CrossrefPubMedGoogle Scholar
  • 4 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.
    CrossrefPubMedGoogle Scholar
  • 5 Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011; 145: 341-355.
    CrossrefPubMedGoogle Scholar
  • 6 Lahoute C, Herbin O, Mallat Z. et al. Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat Rev Cardiol 2011; 8: 348-358.
    CrossrefPubMedGoogle Scholar
  • 7 Perrins CJ, Bobryshev YV. Current advances in understanding of immunopathology of atherosclerosis. Virchows Arch 2011; 458: 117-123.
    CrossrefPubMedGoogle Scholar
  • 8 Bobryshev YV. Dendritic cells and their role in atherogenesis. Lab Invest 2010; 90: 970-984.
    CrossrefPubMedGoogle Scholar
  • 9 Shortman K, Naik SH. Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 2007; 7: 19-30.
    CrossrefPubMedGoogle Scholar
  • 10 Naik SH. Demystifying the development of dendritic cell subtypes, a little. Immunol Cell Biol 2008; 86: 439-452.
    CrossrefPubMedGoogle Scholar
  • 11 Ju X, Clark G, Hart DN. Review of human DC subtypes. Methods Mol Biol 2010; 595: 3-20.
    PubMedGoogle Scholar
  • 12 Miloud T, Hammerling GJ, Garbi N. Review of murine dendritic cells: types, location, and development. Methods Mol Biol 2010; 595: 21-42.
    PubMedGoogle Scholar
  • 13 Geissmann F, Manz MG, Jung S. et al. Development of monocytes, macrophages, and dendritic cells. Science 2010; 327: 656-661.
    CrossrefPubMedGoogle Scholar
  • 14 Geissmann F, Gordon S, Hume DA. et al. Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol 2010; 10: 453-460.
    CrossrefPubMedGoogle Scholar
  • 15 Galkina E, Kadl A, Sanders J. et al. Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent. J Exp Med 2006; 203: 1273-1282.
    CrossrefPubMedGoogle Scholar
  • 16 Weber C, Meiler S, Döring Y. et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T-cell homeostasis in mice. J Clin Invest. 2011. in press
    Google Scholar
  • 17 Liu P, Yu YR, Spencer JA. et al. CX3CR1 deficiency impairs dendritic cell accumulation in arterial intima and reduces atherosclerotic burden. Arterioscler Thromb Vasc Biol 2008; 28: 243-250.
    PubMedGoogle Scholar
  • 18 Bobryshev YV. Dendritic cells in atherosclerosis: current status of the problem and clinical relevance. Eur Heart J 2005; 26: 1700-1704.
    CrossrefPubMedGoogle Scholar
  • 19 Yilmaz A, Lochno M, Traeg F. et al. Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques. Atherosclerosis 2004; 176: 101-110.
    CrossrefPubMedGoogle Scholar
  • 20 Erbel C, Sato K, Meyer FB. et al. Functional profile of activated dendritic cells in unstable atherosclerotic plaque. Basic Res Cardiol 2007; 102: 123-132.
    CrossrefPubMedGoogle Scholar
  • 21 Yilmaz A, Weber J, Cicha I. et al. Decrease in circulating myeloid dendritic cell precursors in coronary artery disease. J Am Coll Cardiol 2006; 48: 70-80.
    CrossrefPubMedGoogle Scholar
  • 22 Van Vre EA, Hoymans VY, Bult H. et al. Decreased number of circulating plasmacytoid dendritic cells in patients with atherosclerotic coronary artery disease. Coron Artery Dis 2006; 17: 243-248.
    CrossrefPubMedGoogle Scholar
  • 23 Van Vre EA, Van Brussel I, de Beeck KO. et al. Changes in blood dendritic cell counts in relation to type of coronary artery disease and brachial endothelial cell function. Coron Art Dis 2010; 21: 87-96.
    CrossrefPubMedGoogle Scholar
  • 24 Millonig G, Niederegger H, Rabl W. et al. Network of vascular-associated dendritic cells in intima of healthy young individuals. Arterioscler Thromb Vasc Biol 2001; 21: 503-508.
    CrossrefPubMedGoogle Scholar
  • 25 Jongstra-Bilen J, Haidari M, Zhu SN. et al. Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J Exp Med 2006; 203: 2073-2083.
    CrossrefPubMedGoogle Scholar
  • 26 Choi JH, Do Y, Cheong C. et al. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J Exp Med 2009; 206: 497-505.
    CrossrefPubMedGoogle Scholar
  • 27 Cybulsky MI, Jongstra-Bilen J. Resident intimal dendritic cells and the initiation of atherosclerosis. Curr Opin Lipidol 2010; 21: 397-403.
    CrossrefPubMedGoogle Scholar
  • 28 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.
    CrossrefPubMedGoogle Scholar
  • 29 Auffray C, Fogg D, Garfa M. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 2007; 317: 666-670.
    CrossrefPubMedGoogle Scholar
  • 30 Landsman L, Bar-On L, Zernecke A. et al. CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 2009; 113: 963-972.
    CrossrefPubMedGoogle Scholar
  • 31 Wu H, Gower RM, Wang H. et al. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation 2009; 119: 2708-2717.
    CrossrefPubMedGoogle Scholar
  • 32 Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003; 19: 71-82.
    CrossrefPubMedGoogle Scholar
  • 33 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.
    CrossrefPubMedGoogle Scholar
  • 34 Zhu SN, Chen M, Jongstra-Bilen J. et al. GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions. The Journal of experimental medicine 2009; 206: 2141-2149.
    CrossrefPubMedGoogle Scholar
  • 35 Shaposhnik Z, Wang X, Weinstein M. et al. Granulocyte macrophage colony-stimulating factor regulates dendritic cell content of atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2007; 27: 621-627.
    CrossrefPubMedGoogle Scholar
  • 36 Ditiatkovski M, Toh BH, Bobik A. GM-CSF deficiency reduces macrophage PPAR-gamma expression and aggravates atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2006; 26: 2337-2344.
    CrossrefPubMedGoogle Scholar
  • 37 Randolph GJ, Potteaux S. Vascular dendritic cells as gatekeepers of lipid accumulation within nascent atherosclerotic plaques. Circulation Res 2010; 106: 227-229.
    CrossrefPubMedGoogle Scholar
  • 38 Paulson KE, Zhu SN, Chen M. et al. Resident Intimal Dendritic Cells Accumulate Lipid and Contribute to the Initiation of Atherosclerosis. Circ Res 2009; 106: 383-390.
    PubMedGoogle Scholar
  • 39 Hansson GK, Hermansson A. The immune system in atherosclerosis. Nature immunology 2011; 12: 204-212.
    CrossrefPubMedGoogle Scholar
  • 40 Alderman CJ, Bunyard PR, Chain BM. et al. Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro-environment?. Cardiovasc Res 2002; 55: 806-819.
    CrossrefPubMedGoogle Scholar
  • 41 Zaguri R, Verbovetski I, Atallah M. et al. 'Danger' effect of low-density lipoprotein (LDL) and oxidized LDL on human immature dendritic cells. Clin Exp Immunol 2007; 149: 543-552.
    CrossrefPubMedGoogle Scholar
  • 42 Nickel T, Schmauss D, Hanssen H. et al. oxLDL uptake by dendritic cells induces upregulation of scavenger-receptors, maturation and differentiation. Atherosclerosis 2009; 205: 442-450.
    CrossrefPubMedGoogle Scholar
  • 43 Cho HJ, Shashkin P, Gleissner CA. et al. Induction of dendritic cell-like phenotype in macrophages during foam cell formation. Physiol Genomics 2007; 29: 149-160.
    CrossrefPubMedGoogle Scholar
  • 44 Angeli V, Llodra J, Rong JX. et al. Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization. Immunity 2004; 21: 561-574.
    CrossrefPubMedGoogle Scholar
  • 45 Gautier EL, Huby T, Saint-Charles F. et al. Conventional dendritic cells at the crossroads between immunity and cholesterol homeostasis in atherosclerosis. Circulation 2009; 119: 2367-2375.
    CrossrefPubMedGoogle Scholar
  • 46 Gautier EL, Huby T, Witztum JL. et al. Macrophage apoptosis exerts divergent effects on atherogenesis as a function of lesion stage. Circulation 2009; 119: 1795-1804.
    CrossrefPubMedGoogle Scholar
  • 47 Han JW, Shimada K, Ma-Krupa W. et al. Vessel wall-embedded dendritic cells induce T-cell autoreactivity and initiate vascular inflammation. Circ Res 2008; 102: 546-553.
    CrossrefPubMedGoogle Scholar
  • 48 Hermansson A, Ketelhuth DF, Strodthoff D. et al. Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med 2010; 207: 1081-1093.
    CrossrefPubMedGoogle Scholar
  • 49 Paulsson G, Zhou X, Tornquist E. et al. Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2000; 20: 10-17.
    CrossrefPubMedGoogle Scholar
  • 50 Sun J, Hartvigsen K, Chou MY. et al. Deficiency of antigen-presenting cell invariant chain reduces atherosclerosis in mice. Circulation 2010; 122: 808-820.
    CrossrefPubMedGoogle Scholar
  • 51 Packard RR, Maganto-Garcia E, Gotsman I. et al. CD11c(+) dendritic cells maintain antigen processing, presentation capabilities, and CD4(+) T-cell priming efficacy under hypercholesterolemic conditions associated with atherosclerosis. Circ Res 2008; 103: 965-973.
    CrossrefPubMedGoogle Scholar
  • 52 Shamshiev AT, Ampenberger F, Ernst B. et al. Dyslipidemia inhibits Toll-like receptor-induced activation of CD8alpha-negative dendritic cells and protective Th1 type immunity. J Exp Med 2007; 204: 441-452.
    CrossrefPubMedGoogle Scholar
  • 53 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.
    CrossrefPubMedGoogle Scholar
  • 54 Kleemann R, Zadelaar S, Kooistra T. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 2008; 79: 360-376.
    CrossrefPubMedGoogle Scholar
  • 55 Binder CJ, Hartvigsen K, Chang MK. et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest 2004; 114: 427-437.
    CrossrefPubMedGoogle Scholar
  • 56 Mallat Z, Besnard S, Duriez M. et al. Protective role of interleukin-10 in atherosclerosis. Circ Res 1999; 85: e17-24.
    CrossrefPubMedGoogle Scholar
  • 57 Ait-Oufella H, Salomon BL, Potteaux S. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006; 12: 178-180.
    CrossrefPubMedGoogle Scholar
  • 58 Taleb S, Romain M, Ramkhelawon B. et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med 2009; 206: 2067-2077.
    CrossrefPubMedGoogle Scholar
  • 59 van Es T, van Puijvelde GH, Ramos OH. et al. Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice. Biochem Biophys Res Commun 2009; 388: 261-265.
    CrossrefPubMedGoogle Scholar
  • 60 Braunersreuther V, Zernecke A, Arnaud C. et al. Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2007; 27: 373-379.
    PubMedGoogle Scholar
  • 61 Gotsman I, Grabie N, Gupta R. et al. Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule. Circulation 2006; 114: 2047-2055.
    CrossrefPubMedGoogle Scholar
  • 62 Grabner R, Lotzer K, Dopping S. et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 2009; 206: 233-248.
    CrossrefPubMedGoogle Scholar
  • 63 Randolph GJ. Emigration of monocyte-derived cells to lymph nodes during resolution of inflammation and its failure in atherosclerosis. Curr Opin Lipidol 2008; 19: 462-468.
    CrossrefPubMedGoogle Scholar
  • 64 Trogan E, Feig JE, Dogan S. et al. Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice. Proc Natl Acad Sci USA 2006; 103: 3781-3786.
    CrossrefPubMedGoogle Scholar
  • 65 Potteaux S, Gautier EL, Hutchison SB. et al. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression. J Clin Invest 2011; 121: 2025-2036.
    CrossrefPubMedGoogle Scholar
  • 66 Luchtefeld M, Grothusen C, Gagalick A. et al. Chemokine receptor 7 knockout attenuates atherosclerotic plaque development. Circulation 2010; 122: 1621-1628.
    CrossrefPubMedGoogle Scholar
  • 67 Zernecke A, Shagdarsuren E, Weber C. Chemokines in atherosclerosis: an update. Arterioscler Thromb Vasc Biol 2008; 28: 1897-1908.
    CrossrefPubMedGoogle Scholar
  • 68 Bernhagen J, Krohn R, Lue H. et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 2007; 13: 587-596.
    CrossrefPubMedGoogle Scholar
  • 69 Tacken PJ, de Vries IJ, Torensma R. et al. Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting. Nat Rev Immunol 2007; 7: 790-802.
    CrossrefPubMedGoogle Scholar
  • 70 Palucka K, Ueno H, Banchereau J. Recent developments in cancer vaccines. J Immunol 2011; 186: 1325-1331.
    CrossrefPubMedGoogle Scholar
  • 71 Hansson GK, Nilsson J. Vaccination against atherosclerosis? Induction of atheroprotective immunity. Semin Immunopathol 2009; 31: 95-101.
    CrossrefPubMedGoogle Scholar
  • 72 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6: 508-519.
    CrossrefPubMedGoogle Scholar
  • 73 Ludewig B, Freigang S, Jaggi M. et al. Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model. Proc Natl Acad Sci USA 2000; 97: 12752-12757.
    CrossrefPubMedGoogle Scholar
  • 74 Habets KL, van Puijvelde GH, van Duivenvoorde LM. et al. Vaccination using oxLDL-pulsed dendritic cells reduces atherosclerosis in LDL receptor-deficient mice. Cardiovasc Res 2009; 85: 622-630.
    PubMedGoogle Scholar
  • 75 Hjerpe C, Johansson D, Hermansson A. et al. Dendritic cells pulsed with malondialdehyde modified low density lipoprotein aggravate atherosclerosis in Apoe(-/-) mice. Atherosclerosis 2010; 209: 436-441.
    CrossrefPubMedGoogle Scholar
  • 76 Hermansson A, Johansson DK, Ketelhuth DF. et al. Immunotherapy with tolerogenic apolipoprotein B-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation 2011; 123: 1083-1091.
    CrossrefPubMedGoogle Scholar
  • 77 Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat Immunol 2004; 5: 1219-1226.
    CrossrefPubMedGoogle Scholar
  • 78 Niessner A, Shin MS, Pryshchep O. et al. Synergistic proinflammatory effects of the antiviral cytokine interferon-alpha and Toll-like receptor 4 ligands in the atherosclerotic plaque. Circulation 2007; 116: 2043-2052.
    CrossrefPubMedGoogle Scholar
  • 79 Niessner A, Weyand CM. Dendritic cells in atherosclerotic disease. Clin Immunol 2010; 134: 25-32.
    CrossrefPubMedGoogle Scholar
  • 80 Sorrentino R, Morello S, Pinto A. Plasmacytoid dendritic cells: from heart to vessels. Int J Vasc Med 2010; 2010: 430318
    PubMedGoogle Scholar
  • 81 Niessner A, Sato K, Chaikof EL. et al. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha. Circulation 2006; 114: 2482-2489.
    CrossrefPubMedGoogle Scholar
  • 82 Marshak-Rothstein A, Busconi L, Rifkin IR. et al. The stimulation of Toll-like receptors by nuclear antigens: a link between apoptosis and autoimmunity. Rheum Dis Clin North Am 2004; 30: 559-574. ix
    CrossrefPubMedGoogle Scholar
  • 83 Ochando JC, Homma C, Yang Y. et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol 2006; 7: 652-662.
    CrossrefPubMedGoogle Scholar
  • 84 Nilsson J, Hansson GK, Shah PK. Immunomodulation of atherosclerosis: implications for vaccine development. Arterioscler Thromb Vasc Biol 2005; 25: 18-28.
    PubMedGoogle Scholar