Asian Cardiovasc Thorac Ann 2006;14:166-169
© 2006 Asia Publishing EXchange Ltd
Role of Dendritic Cells in Atherosclerosis
Ranjit Sharma, MD,
Da-Zhu Li, PhD
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
For reprint information contact: Ranjit Sharma, MD Tel: 86 139 7167 8047 Fax: 86 27 8369 1231, Email: sharmaranjit100{at}hotmail.com, Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
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ABSTRACT
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Atherosclerosis is a lipid-related chronic inflammatory disease in which immune mechanisms play a pivotal role. The lesions are filled with large numbers of immune cells. During the last decade, dendritic cells have been identified in atherosclerotic plaques and are thought to play an important role in atherogenesis. Dendritic cells express major histocompatibility complex I and II, human leukocyte antigen-DR, CD1a, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and co-stimulatory molecule on their surfaces and this explains their unique ability to activate naive T cells. Factors such as oxidized low-density lipoprotein, hypoxia, nicotine, heat shock proteins, and altered nitric oxide synthase activity of the endothelium, all of which cause endothelial dysfunction, have a significant impact on dendritic cell adherence to endothelium and maturation. Mature dendritic cells are capable of presenting antigens to T cells, and activation of T cells leads to release of cytokines, which play an important role in the progression of disease. Drugs such as statins and diltiazem have been shown to protect endothelial function by inhibition of dendritic cell-endothelial cell interaction, and can be applied to delay the progression of cardiovascular diseases.
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INTRODUCTION
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Atherosclerosis is a lipid-related chronic inflammatory disease of the vessel wall, which affects various vascular beds.1 Its pathogenesis involves inflammatory cells, systemic markers, and pro-inflammatory signaling systems. It is well established that atherosclerotic plaques contain immune competent cells, among which monocyte-derived macrophages and T lymphocytes are the most conspicuous. Extensive evidence supports inflammatory/immune activation of plaques as a cause of acute coronary syndromes. Being specialized antigen-presenting cells, dendritic cells (DC) may play an important role in this activation and may affect the initiation and progression of atherosclerosis. Recently, we reported that the function of DC is increased in patients with unstable angina, and the activated function of DC is an important mediator in the inflammatory process leading to plaque instability and vulnerability to rupture.2
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IMMUNE CELLS AND THE PATHOGENESIS OF ATHEROSCLEROSIS
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Macrophages and T cells are common components of atherosclerotic lesions which may also contain mast cells and dendritic cells.3 Macrophages are seen in all stages of atherosclerosis.4 The degree of macrophage infiltration has been shown to distinguish between unstable and stable coronary lesions.5 T cells represent the other main cellular component of atherosclerotic lesions. T cells of both the helper CD4+ and CD8+ types have been detected in human atheroma and have been shown to be immunologically activated.6 The first direct evidence for this activation was the demonstration of human leukocyte antigen-DR expression on the surface of smooth muscle cells adjacent to the T lymphocytes in the lesions. This human lymphocyte antigen expression is induced by interferon-gamma, a product of activated T cells.7 The presence of activated T lymphocytes in the atherosclerotic plaque suggests a local immune response, and it has been postulated that such a response may be directed against local antigens in the plaque. Immunohistochemical analysis has shown that T cells obtained by directional coronary atherectomy of culprit lesions in patients with acute coronary syndromes showed increased expression of interleukin-2 receptors (CD25) compared to T cells obtained from so-called stable lesions.8
Studies during the last decade have identified DC in atherosclerotic plaques. Dendritic cells are present in their immature forms in the arterial wall and become activated during atherogenesis.9–10 Atherosclerosis begins in youth and an accumulation of activated T lymphocytes, DC, macrophages and aberrant major histocompatibility complex class expression on cells can be noticed in the intima predisposed to the development of atherosclerotic lesions later in life, particularly if classical risk factors are present.11 In atherosclerotic lesions, more than 90% of DC co-localized with T cells are located in the neovascularization areas associated with inflammatory infiltrates.12 Dendritic cells are present in the intima of arteries but not in the veins of healthy humans and rabbits, and these DC accumulate most densely in arterial regions that are subjected to major hemodynamic stress by turbulent flow conditions, which are known to predispose to later development of atherosclerosis.13 Dendritic cells are found in aortic atherosclerotic lesions in rats with diet-induced hypercholesterolemia, and they also infiltrate atherosclerotic lesions in apolipoprotein E-deficient mice.14–15 S-100-positive dendritic cells were found in different types of atherosclerotic lesions and are thought to be essential for the stimulation and activation of T cells.9 These observations suggest that DC might be involved in atherosclerosis.
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DENDRITIC CELLS AND THEIR FUNCTIONS
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Dendritic cells, originally described by Steinman and Cohn16 in 1973, play a crucial role in the initiation of the immune response. They are the key antigen-presenting cells and are central to the enhancement and regulation of cell-mediated immune reactions.16 Dendritic cells arise from a common CD34+ progenitor in the bone marrow and constitute a family of cells able to induce primary immune responses.17 Their precursors exit the bone marrow and migrate via the blood stream to take up residence in different peripheral tissues to activate T cells. Dendritic cells express high levels of both class I and class II major histocompatibility complex molecules, human leukocyte antigen-DR, CDIa, and co-stimulatory molecules, and this explains their unique ability to activate naive T cells. The presence of cell adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 on the surfaces of DC implies that they are capable of forming contacts responsible for T cell activation, since vascular cell adhesion molecule-1/very late antigen-4 and intercellular adhesion molecule-1/leukocyte function associated-1 are crucial for T cell activation.12
Dendritic cells also display CD1a on their surfaces, which has recently been recognized as an antigen-presenting molecule in the same sense as the classical histocompatibility complex I and II molecules.18 The capacity of DC to stimulate T cells depends on their stage of maturation: after DC have picked up antigens in their immature phagocytic stage, they move to the regional lymphatic node while undergoing maturation.17 Maturation boosts their capacity to efficiently present antigens to T cells and is mediated by up-regulation of co-stimulatory molecules such as CD86 and CD40. Co-stimulation by the ligands CD80/CD86 and its receptors CD28 on T cells is required for efficient T cell stimulation.19
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RECRUITMENT OF DENDRITIC CELLS TO THE VESSEL WALL
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Altered endothelial function has a significant impact on DC adherence to the endothelium. Endothelial cells exposed to oxidized low-density lipoprotein (LDL), tissue necrosis factor (TNF) alpha, hypoxia, and infection are much more vulnerable to DC attachment and transmigration than non-activated endothelial cells. Endothelial cell apoptosis markedly enhances DC adhesion.20 Endothelial activation increases the expression of adhesion molecules such as CD11/CD18, P-selectin, E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1.21 E- and P-selectins mediate the initial process of endothelial DC rolling.22 The initial contact is followed by the development of firmer adhesion between DC and endothelial cells, which is facilitated by CC-chemokines, lymphocyte function-associated antigen, CD11b, intercellular adhesion molecule-2 and its ligand, the DC-specific C-type lectin, DC-SIGN.23
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DENDRITIC CELL MATURATION AND ITS EFFECTS ON ATHEROSCLEROSIS
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Dendritic cell adhesion and migration can be increased by endothelial activation and it has been demonstrated that DC interaction with endothelial cells is strongly enhanced after blocking endothelial NO synthase activity using the endogenous NO synthase inhibitor asymmetric dimethyl L-arginine.20 These findings support the concept that endothelial activation accelerates DC-mediated immune activation, finally leading to enhanced vascular inflammation. Nicotine activates DC and augments their capacity to stimulate T cell proliferation and cytokine secretion.24 These effects of nicotine may have an influence on the progression of atherosclerotic lesions. Bobryshev and colleagues25 reported that in advanced atherosclerotic lesions, several cell types, including monocytes, macrophages, DC, and smooth muscle cells overexpressed heat shock protein-70. Dendritic cells that overexpressed heat shock protein-70 frequently contacted T cells and also expressed human leucocyte antigen-DR. In early intimal lesions, heat shock protein-70 is overexpressed exclusively by DC, which suggests that DC might be involved in the early phase of atherogenesis.
Oxidized LDL is one of the endogenous activators of the immune response. In vitro studies show that elevated levels of oxidized LDL would favor rapid generation of mature DC from monocytes.26 Autoantibodies to oxidized LDL are considered to have a protective role in atherogenesis. In an experimental model in which an animal was immunized with oxidized LDL, induction of atherosclerosis was not possible.27 Oxidized LDL induces a balanced immunogenic cascade. It was found that mildly oxidized LDL activated the maturation of DC and increased DC-induced T cell activation and proliferation; however, high concentrations of oxidized LDL inhibited DC function, due to increased DC apoptosis.28
Mature dendritic cells are capable of processing and presenting antigen to T cells. Recently, T cell activation in atherosclerotic plaques has been attributed to DC, because of the presence of the large number of DC in plaques, and DC can physically cluster with T cells, which is thought to be essential for stimulation and activation of T cells.29 Antigen-presenting DC-induced T cell activation results in inflammatory amplification through T cell secretion of cytokines, including interferon-gamma, TNF
, and TNFß. Interferon-gamma released from T cells not only primes macrophages for activation but plays an important part in destabilizing atherosclerotic plaques by inhibiting the proliferation of smooth muscle cells and decreasing their synthesis.29 Smooth muscle cell proliferation is also affected by TNF and IL-1. They stimulate further activation of macrophage-induced secretion of matrix metalloproteinase-9 and promote expression of leukocyte adhesion molecules.30
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CAN WE PREVENT ATHEROSCLEROSIS BY BLOCKING DC-ENDOTHELIAL CELL INTERACTION?
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Several studies have revealed that alterations in endothelial function have a significant impact on DC adherence to endothelium. Endothelial activation and DC recruitment may play an important role in atherosclerosis. Delineation of the determinants of DC-endothelial cell interaction may lead to new therapeutic avenues. Inhibition of DC-endothelial cell interaction may have an application in reducing the progression of cardiovascular disease. Recently, Weis and colleagues20 demonstrated that a physiological concentration of 3-hydroxy-3-methylglutaryl-CoA reductase (statin) decreased DC adhesion and transmigration. The results of this study suggest that the adhesion and migration of DC are increased by stimuli known to accelerate atherogenesis. Conversely, augmentation of endothelial NO synthase activity prevents DC adhesion. These findings may provide insight into the inflammatory processes occurring in atherosclerosis. Because DC control immunity, regulating DC-endothelial cell interaction may be relevant to inflammation and atherogenesis. Statins increase endothelial NO bioactivity, decrease endothelial apoptosis, and inhibit smooth muscle cell proliferation.31 Thus, by enhancing NO synthesis, statins may diminish inflammatory activity in the early phase of atherosclerosis. Bachetoni and colleagues32 reported that diltiazem decreases DC-dependent T cell activation and plays an important role in preventing atherosclerosis. Diltiazem-induced DC have an impaired responsiveness to lipopolysaccharide and the CD40 ligand because they produce decreased levels of interleukin-12 and reveal a reduced ability to stimulate alloreactive T cell responses.
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CONCLUSION
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Atherosclerosis is an immunoinflammatory disease. Endothelial dysfunction and injury are the basis of the onset of the atherosclerotic process. Endothelial adhesion and migration of DC is increased by stimuli known to accelerate atherosclerosis. Such factors include viral and bacterial antigens, oxidized LDL, heat shock protein, hypoxia, and altered NO synthase activity of the endothelium. DC-induced T cell activation followed by cytokine production contributes to coronary plaque instability and vulnerability towards rupture. Statins and diltiazem have been shown to protect endothelial function by inhibition of DC-endothelial cell interaction, and have an application in reducing the progression of cardiovascular disease.
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REFERENCES
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|---|
- Ross R. Atherosclerosis—an inflammatory disease. N Eng J Med 1999;340:115–26.[Free Full Text]
- Ranjit S, Dazhu L, Qiutang Z, Yibo F, Yushu L, Xiang W, et al. Differentiation of dendritic cells in monocyte cultures isolated from patients with unstable angina. Int J Cardiol 2004;97:551–5.[Medline]
- Hansson GK. Immune mechanism in atherosclerosis. Arterioscler Thromb Vasc Biol 2001;21:1876–90.[Abstract/Free Full Text]
- Hansson GK, Libby P, Schonbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 2002;91:281–91.[Abstract/Free Full Text]
- Gown AM, Tsukada T, Ross R. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol 1986;125:191–207.[Abstract]
- Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 1989;135:169–75.[Abstract]
- Jonasson L, Holm J, Skalli O, Gabbiani G, Hansson GK. Expression of class II transplantation antigen on vascular smooth muscle cells in human atherosclerosis. J Clin Invest 1985;76:125–31.[Medline]
- van der Wal AC, Piek JJ, de Boer OJ, Koch KT, Teeling P, van der Loos CM, et al. Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes. Heart 1998;80:14–8.[Abstract/Free Full Text]
- Bobryshev YV, Lord RS. S-100 positive cells in human arterial intima and in atherosclerotic lesions. Cardiovas Res 1995;29:689–96.[Medline]
- Link A, Bohm M. Potential role of dendritic cells in atherogenesis. Cardiovasc Res 2002;55:708–9.[Free Full Text]
- Millonig G, Malcom GT, Wick G. Early inflammatory-immunological lesions in juvenile atherosclerosis from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY)–study. Atherosclerosis 2002;160:441–8.[Medline]
- Bobryshev YV, Lord RS. Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local immune-inflammatory reactions. Cardiovasc Res 1998;37:799–810.[Abstract/Free Full Text]
- Millonig G, Niederegger H, Rabl W, Hochleitner BW, Hoefer D, Romani N, et al. Network of vascular-associated dendritic cells in intima of healthy young individuals. Arterioscler Thromb Vasc Biol 2001;21:503–8.[Abstract/Free Full Text]
- Ozmen J, Bobryshev YV, Lord RS, Ashwell KW. Identification of dendritic cells in aortic atherosclerotic lesions in rats with diet-induced hypercholesterolaemia. Histol Histopathol 2002;17:223–37.[Medline]
- Bobryshev YV, Taksir T, Lord RS, Freeman MW. Evidence that dendritic cells infiltrate atherosclerotic lesions in apolipoprotein E-deficient mice. Histol Histopathol 2001;16:801–8.[Medline]
- Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 1973;137:1142–62.[Abstract]
- Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245–52.[Medline]
- Beckman EM, Brenner MB. MHC class I-like, class II-like and CD1 molecules: distinct roles in immunity. Immunol Today 1995;16:349–51.[Medline]
- Carreno BM, Collins M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 2002;20:29–53.[Medline]
- Weis M, Schlichting CL, Engleman EG, Cooke JP. Endothelial determinants of dendritic cell adhesion and migration: new implications for vascular diseases. Arterioscler Thromb Vasc Biol 2002;22:1817–23.[Abstract/Free Full Text]
- Cooke JP, Dzau VJ. Nitric oxide syntheses: role in the genesis of vascular disease. Annu Rev Med 1997;48:489–509.[Medline]
- D’Amico G, Bianchi G, Bernasconi S, Bersani L, Piemonti L, Sozzani S, et al. Adhesion, transendothelial migration, and reverse transmigration of in vitro cultured dendritic cells. Blood 1998;92:207–14.[Abstract/Free Full Text]
- Geijtenbeek TB, Krooshoop DJ, Bleijs DA, van Vliet SJ, van Duijnhoven GC, Grabovsky V, et al. DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking. Nat Immunol 2000;1:353–7.[Medline]
- Aicher A, Heeschen C, Mohaupt M, Cooke JP, Zeiher AM, Dimmeler S. Nicotine strongly activates dendritic cell-mediated adaptive immunity: potential role for progression of atherosclerotic lesions. Circulation 2003;107:604–11.[Abstract/Free Full Text]
- Bobryshev YV, Lord RS. Expression of heat shock protein-70 by dendritic cells in the arterial intima and its potential significance in atherogenesis. J Vasc Surg 2002;35:368–75.[Medline]
- Perrin-Cocon L, Coutant F, Agaugue S, Deforges S, Andre P, Lotteau V. Oxidized low-density lipoprotein promotes mature dendritic cell transition from differentiating monocyte. J Immunol 2001;167:3785–91.[Abstract/Free Full Text]
- Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet 1994;344:793–5.[Medline]
- Alderman CJ, Bunyard PR, Chain BM, Foreman JC, Leake DS, Katz DR. Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro-environment? Cardiovascular Res 2002;55:806–19.[Abstract/Free Full Text]
- Inaba K, Steinman RM. Accessory cell-T lymphocyte interactions. Antigen-dependent and -independent clustering. J Exp Med 1986;163:247–61.[Abstract/Free Full Text]
- Neri Serneri GG, Prisco D, Martini F, Gori AM, Brunelli T, Poggesi L, et al. Acute T-cell activation is detectable in unstable angina. Circulation 1997;95:1806–12.[Abstract/Free Full Text]
- Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis. Circulation 2002;105:739–45.[Abstract/Free Full Text]
- Bachetoni A, D’Ambrosio A, Mariani P, Cortesini R, Quintieri F. Diltiazem impairs maturation and functions of human dendritic cells. Hum Immunol 2002;63:524–33.[Medline]
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ABSTRACT
INTRODUCTION
