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The immune response in atherosclerosis: a double-edged sword

The immune response in atherosclerosis: a double-edged sword Göran K. Hansson * and Peter Libby Abstract Immune responses participate in every phase of atherosclerosis. There is increasing evidence that
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The immune response in atherosclerosis: a double-edged sword Göran K. Hansson * and Peter Libby Abstract Immune responses participate in every phase of atherosclerosis. There is increasing evidence that both adaptive and innate immunity tightly regulate atherogenesis. Although improved treatment of hyperlipidaemia reduces the risk for cardiac and cerebral complications of atherosclerosis, these remain among the most prevalent of diseases and will probably become the most common cause of death globally within 15 years. This Review focuses on the role of immune mechanisms in the formation and activation of atherosclerotic plaques, and also includes a discussion of the use of inflammatory markers for predicting cardiovascular events. We also outline possible future targets for prevention, diagnosis and treatment of atherosclerosis. Plaque An atherosclerotic lesion consisting of a fibrotic cap surrounding a lipid-rich core. The lesion is the site of inflammation, lipid accumulation and cell death. Also known as an atheroma. *Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, SE-17176, Sweden. Leducq Transatlantic Network of Excellence in Cardiovascular Research, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA. Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. Correspondence to P.L. doi: /nri1882 Published online 16 June 2006 Atherosclerosis is an inflammatory disease characterized by intense immunological activity, which increasingly threatens human health worldwide 1. Atherosclerosis involves the formation in the arteries of lesions that are characterized by inflammation, lipid accumulation, cell death and fibrosis. Over time, these lesions, which are known as atherosclerotic plaques, mature and gain new characteristics. Although clinical complications of atherosclerosis can arise from plaques causing flow-limiting stenoses, the most severe clinical events follow the rupture of a plaque, which exposes the prothrombotic material in the plaque to the blood and causes sudden thrombotic occlusion of the artery at the site of disruption. In the heart, atherosclerosis can lead to myocardial infarction and heart failure; whereas in the arteries that perfuse the brain, it can cause ischaemic stroke and transient ischaemic attacks. If atherosclerosis affects other arterial branches, it can result in renal impairment, hypertension, abdominal aortic aneurysms and critical limb ischaemia. As our knowledge of this disease increases, we increasingly recognize that there is no simple answer to the question of whether the immune response promotes or retards atherogenesis. Indeed, the two arms of the immune response can either promote or attenuate aspects of atherosclerosis and its complications. This Review summarizes our current understanding of the role of adaptive immunity in atherosclerosis and, in particular, weighs the evidence regarding the yin and yang of the immune response at various places and times in the evolution of this lengthy and complex disease. We do not discuss the arteriosclerosis of allografted transplants, which is a distinct disease with a unique pathogenesis, although it might represent an extreme case of immune-driven arteriopathy. Immunological features of atherosclerosis In humans, atherosclerotic plaques contain blood-borne inflammatory and immune cells (mainly macrophages and s), as well as vascular endothelial cells, smooth muscle cells, extracellular matrix, lipids and acellular lipid-rich debris 2. These lesions typically present as asymmetrical focal thickenings of the intima, which is the innermost layer of the artery (FIG. 1). Accumulation of immune cells and lipid droplets in the intima occurs during the first stage of plaque formation. Lipid-laden macrophages, known as foam cells, outnumber other cells in early plaques (which are known as fatty streaks), but these nascent plaques also contain s. Fatty streaks are prevalent in young individuals, never cause symptoms, and can progress into mature atherosclerotic plaques or disappear with time. Mature plaques (also known as atheromas) have a more complex structure than fatty streaks (FIG. 1). In the centre of a plaque, foam cells and extracellular lipid droplets form a core region that is surrounded by a cap of smooth muscle cells and a collagen-rich matrix 2. Other cell types present in plaques include dendritic cells (DCs) 3, mast cells 4, a few B cells 2 and probably natural killer T (NKT) cells. The shoulder region of the plaque, which is where it grows, and the interface between the cap and the core have particularly abundant accumulations of s and macrophages 2. Many of these immune cells show signs of activation and produce proinflammatory cytokines such as interferon-γ (IFNγ) and 508 JULY 2006 VOLUME 6 Blood-vessel lumen Endothelial cell Normal artery Shoulder Intima Elastic lamina Media Media Cellular debris and cholesterol Cholesterol Dead cell Dendritic cell Foam cell Macrophage Mast cell Monocyte Smooth muscle cell Figure 1 Cellular composition of atherosclerotic plaques. The atherosclerotic plaque has a core containing lipids (which include esterified cholesterol and cholesterol crystals) and debris from dead cells. Surrounding it, a fibrous cap containing smooth muscle cells and collagen fibres stabilizes the plaque. Immune cells including macrophages, s and mast cells populate the plaque, and are frequently in an activated state. They produce cytokines, proteases, prothrombotic molecules and vasoactive substances, all of which can affect plaque inflammation and vascular function. Until complications occur, an intact endothelium covers the plaque. Myocardial infarction An episode of acute cardiac ischaemia that leads to death of heart muscle cells. It is usually caused by a thrombotic atherosclerotic plaque. Ischaemic stroke An episode of acute regional ischaemia in the brain leading to nerve-cell death. It is usually caused by thrombi or emboli from atherosclerotic plaques. Aneurysm The local dilatation of an artery caused by weakening of the artery wall. Some, but not all, aneurysms are caused by atherosclerosis. Intima The innermost layer of an artery, which consists of loose connective tissue and is covered by a monolayer of endothelium. Atherosclerotic plaques form in the intima. Fibrous cap A structure composed of a dense collagen-rich extracellular matrix with occasional smooth muscle cells, macrophages and s that typically overlies the characteristic central lipid core of plaques. tumour-necrosis factor (TNF) 5. With time, the plaque can progress into an even more complex lesion, the lipid core of which has become a paucicellular pool of cholesterol deposits surrounded by a fibrous cap of varying thickness. The fibrous cap prevents contact between the blood and the pro-thrombotic material in the lesion (FIG. 1). Disruption of the cap can lead to thrombosis and many of the adverse clinical outcomes associated with atherosclerosis. Models of atherogenesis in mutant mice Direct analysis of the early phases of human athero sclerosis presents obvious obstacles. Therefore, systematic investigation of the mechanisms that initiate athero sclerosis relies on animal models of the disease. The available observations indicate that there is substantial overlap between disease development in these animal models and the human disease. Two strains of genetically altered mice have been particularly fruitful in this regard. Apoe / mice lack apolipoprotein E (APOE; which is a key component in cholesterol metabolism), and develop spontaneous hypercholesterolaemia and atherosclerotic disease (which is exacerbated by an atherogenic diet) that progresses to myocardial infarction and stroke 6,7. Low-density-lipoprotein receptor (LDLR)-deficient mice respond to being fed with fat by developing hypercholesterolaemia and atherosclerotic plaques 8. The crossbreeding of these mice with mice that carry deletions in genes encoding crucial components of the immune system has provided important information on the role of the immune system in the pathogenesis of atherosclerosis. In addition, bone-marrow transplantation of, and spleen-cell transfer to, Apoe / or Ldlr / mice has offered insights into the role of specific populations of bone-marrow-derived cells in disease development. Immune-cell recruitment initiates atheroscleroticplaque formation. In experimental animals, endothelial cells in the arteries express leukocyte adhesion molecules, in particular vascular cell-adhesion molecule 1 (VCAM1), as part of the initial vascular response to cholesterol accumulation in the intima 9 (FIG. 2a). The patchy distribution of adhesion-molecule expression corresponds to the subsequent position at which fatty streaks form 10. This patchy pattern of expression probably reflects haemodynamic factors, because the shear stresses and disturbed fluid flows vary over the arterial bed in a similar way to the predilection sites for atherosclerosis. Interestingly, exposing cultured endothelial cells to oscillatory shear stress that mimics arterial blood flow increases the expression of several leukocyte adhesion molecules 11. Shortly after VCAM1 induction, monocytes and s enter the arterial intima (FIG. 2a). Under the influence of macrophage colony-stimulating factor (M-CSF) produced by endothelial cells and smooth muscle cells 12, the monocytes differentiate into macrophages 13 (FIG. 2b) and s can undergo antigen-dependent activation (FIG. 2c; see later). Interestingly, VCAM1 expression by the endothelium ceases after a few weeks, but smooth muscle cells begin to express this adhesion molecule 14. Expression of VCAM1 and other adhesion molecules by smooth muscle cells might promote the recruitment and retention of mononuclear cells in the arterial intima. NATURE REVIEWS IMMUNOLOGY VOLUME 6 JULY a LDL VLA4 VCAM1 Monocyte Blood-vessel lumen Endothelial cell d Increased adhesion molecules Increased permeability Increased propensity for thrombus formation Endothelial cell oxldl b Chemokine receptor Chemokine TLR Endothelial cell 1 cell CD40L IFNγ TNF CD40 Macrophage Proteases Pro-inflammatory mediators LPS, HSP60 or oxldl Scavenger receptor oxldl TCR MHC class II M-CSF Smooth muscle cell Pro-inflammatory cytokines Proteases Procoagulants Pro-apoptotic factors Monocyte Macrophage Foam cell Decreased collagen production Decreased proliferation c Endothelial cell e Endothelial cell 1 cell IL-12 IL-15 IL-18 CD4 + TCR MHC class II 2 cell or regulatory IL-10 TGFβ TGFβ 1 cell Macrophage APC Smooth muscle cell Decreased inflammation Figure 2 Recruitment and activation of immune cells in atherosclerotic plaques. a Low-density lipoprotein (LDL) diffuses from the blood into the innermost layer of the artery, where LDL particles can associate with proteoglycans of the extracellular matrix. The LDL of this extracellular pool is modified by enzymes and oxygen radicals to form molecules such as oxidized LDL (oxldl). Biologically active lipids are released and induce endothelial cells to express leukocyte adhesion molecules, such as vascular cell-adhesion molecule 1 (VCAM1). Monocytes and s bind to VCAM1-expressing endothelial cells through very late antigen 4 (VLA4) and respond to locally produced chemokines by migrating into the arterial tissue. b Monocytes differentiate into macrophages in response to local macrophage colony-stimulating factor (M-CSF) and other stimuli. Expression of many pattern-recognition receptors increases, including scavenger receptors and Toll-like receptors (TLRs). Scavenger receptors mediate macrophage uptake of oxldl particles, which leads to intracellular cholesterol accumulation and the formation of foam cells. TLRs bind lipopolysaccharide (LPS), heat-shock protein 60 (HSP60), oxldl and other ligands, which instigates the production of many pro-inflammatory molecules by macrophages. c s undergo activation after interacting with antigen-presenting cells (APCs), such as macrophages or dendritic cells, both of which process and present local antigens including oxldl, HSP60 and possibly components of local microorganisms. A T helper 1 ( 1)-cell-dominated response ensues, possibly owing to the local production of interleukin-12 (IL-12), IL-18 and other cytokines. Antigen presentation and 1-cell differentiation might also occur in regional lymph nodes. d 1 cells produce inflammatory cytokines including interferon-γ (IFNγ ) and tumour-necrosis factor (TNF) and express CD40 ligand (CD40L). These messengers prompt macrophage activation, production of proteases and other pro-inflammatory mediators, activate endothelial cells, increase adhesion-molecule expression and the propensity for thrombus formation, and inhibit smooth-muscle-cell proliferation and collagen production. e Plaque inflammation might be attenuated in response to the anti-inflammatory cytokines IL-10 and transforming growth factor-β (TGFβ), which are produced by several cell types including regulatory s, macrophages, and for TGFβ, also vascular cells and platelets. TCR, T-cell receptor. 510 JULY 2006 VOLUME 6 Scavenger receptors Cell-membrane proteins that take up oxidatively or otherwise modified low-density lipoproteins. Experiments using genetically altered mice show that leukocyte adhesion molecules participate in the initiation of atherosclerosis. Apoe / mice that are also deficient for both endothelial-cell selectin (E-selectin) and platelet selectin (P-selectin) have reduced severity of atherosclerosis 15. Similarly, Ldlr / mice that express a truncated form of VCAM1 with impaired function develop less severe disease than those expressing wild-type VCAM1 (REF. 16). Such studies use truncated VCAM1 because complete VCAM1 deficiency is lethal at the embryonic stage. In addition to the expression of adhesion molecules, several chemokines produced by vascular cells guide the recruitment of immune cells (FIG. 2a). Data obtained using knockout mice show a key role for CC-chemokine ligand 2 (CCL2; also known as MCP1) and its receptor, CC-chemokine receptor 2 (CCR2), in the initiation of atherosclerosis 17,18. Indeed, absence of CCL2 or CCR2 limits the entry of monocytes and s into the arterial intima and inhibits atherogenesis. Macrophages and vascular cells of the forming plaque also produce the T-cell attractants CCL5 (also known as RANTES), CXC-chemokine ligand 10 (CXCL10; also known as IP10) and CXCL11 (also known as ITAC) 19, the mastcell attractant CCL11 (also known as eotaxin) 20 and also the Janus molecule CXCL16, which can function as both a scavenger receptor and a chemokine 21. Administration of a blocking form of CCL5 attenuates atherogenesis in mice 22. Atherosclerotic plaques in humans and mice also express another chemokine, the cell-surface anchored CX 3 -chemokine ligand 1 (CX 3 CL1; also known as fractalkine), which is a transmembrane protein preferentially expressed by smooth muscle cells. CX 3 CL1 that is shed by proteolysis can engage CX 3 -chemokine receptor 1 (CX 3 CR1), which is expressed by monocytes and macrophages. Ligation of CX 3 CR1 on blood-borne monocytes stimulates their migration to the artery wall and contributes to atherogenesis, as indicated by studies using mice deficient for both APOE and CX 3 CR1 (REFS 23,24). Innate immunity and lipid accumulation Monocyte-derived macrophages abound in plaques and are outnumbered only by vascular smooth muscle cells in some plaques. Several phenotypes of macrophage are found in plaques, including inflammatory macrophages and also foam cells, which develop when cholesteryl esters accumulate in the cytosol of intimal macrophages (FIG. 2b). Cholesterol derives from lipoproteins that have undergone oxidation or enzymatic modification in the tissue. This renders the lipoprotein particle amenable to uptake by macrophages that express scavenger receptors 25, a family of proteins that includes CD36, CD68, CXCL16, lectin-type oxidized low-density lipoprotein receptor 1 (LOX1), scavenger receptor A (SR-A) and SR-B1. Scavenger receptors are pattern-recognition receptors (PRRs) that mediate internalization and lysosomal degradation of modified lipoprotein particles, lipopolysaccharide, fragments of malaria parasites and apoptotic bodies 26. Uptake by scavenger receptors does not lead directly to inflammation but can lead to MHC-class-II-restricted antigen presentation of internalized material, thereby linking innate and adaptive immunity 27. Considering their role in the formation of foam cells, one would expect scavenger receptors to have an important, if not crucial, role in atherogenesis. However, recent results showing increased, rather than decreased, atherosclerosis in mice lacking CD36, CXCL16 or SR-A have cast doubt on this conclusion 28. This might be because receptor-mediated internalization of modified lipoproteins by macrophages can facilitate the eventual elimination of these particles from plaques through high-density-lipoprotein-dependent mechanisms 29. If, as a result of the absence of foam cells, this clearance of modified lipoprotein did not occur, removal of such lipids from plaques would be less efficient and the accumulation of extracellular cholesterol in the lipid pool might be more detrimental than the presence of foam cells. Whereas scavenger receptors mediate internalization, degradation and antigen presentation of ligands, Toll-like receptors (TLRs) can elicit inflammatory responses directly 30. The many TLR-family members that can be detected in plaques are expressed mainly by macrophages and endothelial cells 31. By contrast, in the normal artery wall, only TLR2 and TLR4 are expressed by endothelial cells and the underlying smooth muscle cells do not express TLRs. Therefore, plaque formation causes a considerable increase in the repertoire of PRRs expressed by the artery wall. A broad range of pathogen-associated molecular patterns can ligate the different TLRs 30. Among them, microbial components, heat-shock proteins (HSPs) and unmethylated CpG DNA might be directly relevant to athero genesis because several microorganisms are associated with atherosclerosis. In addition, some data indicate that endogenous HSP60 and oxidized LDL (oxldl) bind TLR4 CD14 complexes and elicit inflammatory responses Following ligation, TLRs activate nuclear factor-κb (NF-κB) and mitogen-activated protein kinase activator protein 1 signalling pathways 30,32. Direct immuno histochemical analysis has shown that a large proportion of the TLR4-expressing cells in human plaques have nuclear translocation of NF-κB, which is consistent with a role for TLR4 ligation in inflammatory activation in the plaques 31. The response downstream of TLR ligation in the plaque probably involves the secretion of pro-inflammatory cytokines and matrix metalloproteinases (MMPs), as well as the production of low-molecular-weight inflammatory mediators such as nitric oxide and endothelin-1 (REF. 30). Genetic deficiency of TLR4 or its signal-transducing adaptor molecule myeloid differentiation primary-response gene 88 (MyD88) reduces plaques in mice 35,36. s promote atherogenesis Human atherosclerotic plaques contain numerous s. In a plaque, ~40% of the cells express macrophage markers, ~10% are CD3 + s and most of the remainder have the characteristics of smooth muscle NATURE REVIEWS IMMUNOLOGY VOLUME 6 JULY Vasa vasorum Small nutrient vessels in the normal adventitia and outer media of the artery wall, which can also give rise to microvessels in the plaque. cells 2. Small populations of mast cells, B cells and DCs occur in plaques and, together with s, monocytes and macrophages, might traffic between the blood in the arterial lumina, the lesioned artery wall, the vasa vasorum microvessels that penetrate the artery and the
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