STATE-OF-THE-ART PAPER
The CD40/CD40 Ligand SystemLinking Inflammation With Atherothrombosis
Charalambos Antoniades, MD*,
Constantinos Bakogiannis, MD,
Dimitris Tousoulis, MD, PhD,
Alexios S. Antonopoulos, MD and
Christodoulos Stefanadis, MD
1st Department of Cardiology, University of Athens Medical School, Athens, Greece
Manuscript received December 30, 2008;
revised manuscript received March 5, 2009,
accepted March 10, 2009.
* Reprint requests and correspondence: Dr. Charalambos Antoniades, 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Ilias 8, Gerakas Attikis, 153 44, Athens, Greece (Email: antoniades{at}vodafone.net.gr).
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Abstract
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The role of CD40/CD40 ligand (CD40L) in atherothrombosis is now widely accepted. However, the exact mechanisms linking the CD40/CD40L system and the soluble form of CD40 ligand (sCD40L) with atherothrombosis are currently a topic of intensive research. CD40L and sCD40L belong to the tumor necrosis factor superfamily, and they are molecules with a dual prothrombotic and proinflammatory role. They are expressed in a variety of tissues such as the immune system (in both B and T cells), the vascular wall, and activated platelets. Soluble CD40L has multiple autocrine, paracrine, and endocrine actions, and it may trigger key mechanisms participating in atherothrombosis. CD40/CD40L may participate in the development of coronary atherosclerosis and the triggering of acute coronary syndromes, while sCD40L seems to have a prognostic role not only in subjects with advanced atherosclerosis but also in the general population. Although conventional cardiovascular medication such as antiplatelet therapy, statins, angiotensin-converting enzyme inhibitors, and many others have been shown to reduce both sCD40L and cardiovascular risk, it is still unclear whether specific treatments targeting the CD40/CD40L system will prove to be beneficial against atherothrombosis in the near future.
Key Words: CD40 • CD40L • atherothrombosis • atherogenesis • inflammation • endothelium
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Abbreviations and Acronyms
| | ACS = acute coronary syndrome | | AMI = acute myocardial infarction | | CAD = coronary artery disease | | CD40L = CD40 ligand | | EC = endothelial cell | | GP = glycoprotein | | IL = interleukin | | sCD40L = soluble CD40 ligand | | SMC = smooth muscle cell |
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During the last decade, the links between the immune system and atherothrombosis have been well documented, in a way that atherosclerosis is now considered to be an inflammatory disease (1). Therefore, as atherosclerosis has become an epidemic in the Western world, the investigation of the key inflammatory mechanisms involved in atherogenesis is crucial for the design of therapeutic strategies targeting cardiovascular disease.
Over the recent years, it has been well established that interactions between CD40 and its immunomodulating ligand (CD40L), expressed in a variety of cell types including platelets, vascular wall cells, and immune cells, are actively involved in atherogenetic and thrombotic mechanisms and may serve as a link between inflammation, atherosclerosis, and thrombosis (2).
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Structure of CD40/CD40L and Regulation of its Expression
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CD40 is a type I transmembrane protein receptor and a member of the tumor necrosis factor superfamily, and its gene is located in chromosome 20 (q12-q13.2) (2). Despite the initial suggestion that CD40 exists as a dimer that is being trimerized after CD40L binding, recent studies described CD40 as a constitutional trimer complex on cell surface (Fig. 1) (3).
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Figure 1 Structure of CD40 Receptor, CD40L, and sCD40L
The CD40 protein, which is a type I transmembrane receptor, exists in trimers, and this trimerization is crucial for its activation. The extracellular region of CD40 is cysteine-rich (consisting of 20 residues). The CD40 protein consists of 4 cysteine-rich domains, and every domain is divided into 2 cysteine modules (A1, A2, B1, B2). The CD40 ligand (CD40L) protein is a type II membrane protein with an intracellular amino terminus and an external carboxy terminus. Its extracellular region belongs to the tumor necrosis factor (TNF) superfamily. The CD40L is stored in  -granules in unstimulated platelets but rapidly translocates to the platelet surface when platelets are activated. The surface-expressed CD40L is then cleaved and shed from the platelet surface as soluble CD40 ligand (sCD40L). C = C-terminal; N = N-terminal.
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The B cells are the main cell type expressing CD40; however, CD40 is also expressed on other immunity cells, epithelial cells, fibroblasts, and vascular wall cells such as endothelial cells (ECs) and smooth muscle cells (SMCs), as well as in platelets (4). In addition, the majority of these cells also coexpress the CD40L receptor. Expression of CD40 is induced by proinflammatory stimuli, such as interleukin (IL)-1, -3, and -4, tumor necrosis factor-alpha, and interferon- . CD40 is regularly up-regulated within 6 to 12 h after the initial stimulation, remaining on the cell surface for 24 to 72 h (4). Transcriptional factors, such as nuclear factor-kappa B and activator of transcription kinases, are known to regulate CD40 expression (4). Similarly, proinflammatory cytokines and oxidized low-density lipoprotein induce the expression of CD40L gene, which is located at chromosome X (q26.3-q27.1) (5).
After its ligation, CD40 is activated and the receptor is internalized into the cell (2). The activated receptor then binds to members of the tumor necrosis factor receptor–associated factor family and stimulate downstream signaling pathways, including nuclear factor-kappa B, with subsequent up-regulation of proinflammatory and proatherogenic genes (6).
Platelets express CD40L after stimulation with a wide range of platelet activators, such as thrombin and thrombin receptor agonists, for example, collagen, phorbol myristate acetate, and so forth (7). The first studies reported that CD40L expression on platelet surface is dependent on intracellular calcium (Ca2+) concentrations and protein kinase C activation (7). Elevated release of soluble CD40 ligand (sCD40L) has also been observed in platelets from diabetic patients after stimulation with thrombin or thrombin receptor activation peptide (8). It was also found that insulin resistance as well as glucose and advanced glycation end products induce sCD40L release from platelets and increase CD40L expression in murine megakaryocytes (8). Finally, platelet CD40/CD40L expression is also partly regulated by nitric oxide signaling (9). Indeed, as reported by Schafer et al. in an elegant clinical study (9) and in an animal model (10), inhibition of nitric oxide synthase in humans results in reduced phosphorylation of platelet vasodilator-stimulated phosphoprotein, and induces platelet activation that overexpress CD40. A similar overexpression of CD40 was also observed in streptozotocin-induced diabetic mice, suggesting that diabetes may result in platelet activation and CD40 overexpression partly by decreasing nitric oxide bioavailability (10).
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CD40L in Stable and Acute Coronary Syndromes (ACS): Insights From Basic Science
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Atherogenesis and plaque stability.
CD40/CD40L expression is known to be up-regulated in atheroma-associated cells but the exact regulating mechanisms remain largely unknown (5,11). In vitro studies have shown that CD40/CD40L interactions on the EC surface result in endothelium and SMC activation and subsequent adhesion molecules expression, an initiating step in atherogenesis (5,11). In addition, recent evidence suggests that CD40/CD40L has a role in dendritic cells and T-lymphocytes interactions inside the vascular wall (12). Indeed, mapping of activated dendritic cells in human carotid and coronary atheroma demonstrated that CD40L affects dendritic cell maturation; activated and fully mature dendritic cells regulate T-cell infiltration, characteristic for unstable coronary atheroma (13). Furthermore, sCD40L has an unfavorable effect on the vascular redox state and endothelium-dependent relaxation, through activation of specific redox-sensitive intracellular pathways. Cell and animal studies demonstrate that CD40L destabilizes endothelial nitric oxide synthase messenger ribonucleic acid and increases vascular oxygen production (14). Therefore, proinflammatory cytokines, reduced nitric oxide bioavailability, and overexpression of adhesion molecules promote leukocyte recruitment and migration into tunica media, participating in atheroma formation (Fig. 2) (11). In addition, interactions between CD40L and CD40 also affect the release of adipokines from adipocytes, contributing to atherogenesis (15).
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Figure 2 CD40/CD40L and Atherothrombosis
Activated platelets express CD40 ligand (CD40L), which is then cleaved and released as soluble CD40 ligand (sCD40L). The sCD40L binds to circulating monocytes through both its receptor CD40 and through monocyte/macrophage integrin Mac-1, promoting their adhesion to vascular endothelium. The sCD40L also binds to CD40 on endothelial cell (EC) surfaces, which are then activated (by triggering the overexpression of transcriptional factors such as nuclear factor-kappa B [NF- β], activator protein [AP]-1, and others) to express adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) on EC surfaces. These molecules mediate the adhesion and transmigration of monocytes to subendothelial space. Activated ECs and smooth muscle cells (SMCs) also produce proinflammatory molecules such as monocyte chemoattractant protein (MCP)-1 and interleukins (ILs); they release prothrombotic mediators such as tissue factor; and they overexpress enzymes generating reactive oxygen species (ROS). The ROS oxidize low-density lipoprotein (LDL) to oxidized low-density lipoprotein (Ox-LDL) which is up-taken by activated macrophages, which are turned into foam cells. CD40L also activates SMCs and fibroblasts, which are proliferated and migrate to further induce atherogenesis. Red rectangles = E-selectin; red receptors = Mac-1; yellow triangles = VCAM; and blue triangles = ICAM. MMP = matrix metalloproteinase; NO = nitric oxide; VSMC = vascular smooth muscle cells.
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Further to the interaction between CD40L and CD40, Zirlik et al. (16) demonstrated that sCD40L also interacts with the monocyte/macrophage integrin Mac-1, resulting in Mac-1–dependent adhesion and migration of inflammatory cells. In addition, CD40L–/– mice show significantly reduced invasion of inflammatory cells into the peritoneal cavity compared with CD40–/– and wild-type controls, suggesting the CD40L promotes atherogenesis partly independently of its classic receptor CD40 (Fig. 2) (16).
Evidence suggests that CD40/CD40L interactions induce the expression of matrix metalloproteinases that degrade interstitial collagen and the thin fibrous cap of atheromatous plaques, leading to plaque instability and rupture (11). Indeed, inhibition of CD40L signaling enhances atheroma collagen content in mice (11), whereas it has been suggested that CD40L triggers apoptosis and induces the formation of necrotic core in atherosclerotic plaque (11). Furthermore, recent evidence suggests that CD40/CD40L interactions promote in vivo angiogenesis by up-regulating local vascular endothelial growth factor and basic fibroblastic growth factor expression, affecting in this way intraplaque neovascularization and plaque vulnerability (17).
Platelet activation and thrombus formation.
Further to atheroma formation and plaque weakening, CD40/CD40L interactions have an eminent role in thrombotic events after plaque rupture. The CD40/CD40L interactions induce tissue factor expression on macrophages and ECs and diminish thrombomodulin expression, favoring a local procoagulant and prothrombotic status (18). In addition, the inhibitory role of sCD40L on EC-derived nitric oxide bioavailability may further promote local prothrombotic state (14). Finally, CD40/CD40L interaction inhibits EC migration at the site of the plaque erosion, blocking the re-endothelization process (11).
Platelets are the main source of sCD40L, being responsible for >95% of circulating sCD40L levels (Fig. 1) (19). CD40L stabilizes arterial thrombi by a beta-3 integrin-dependent mechanism that results in platelet activation by outside-in signaling (Fig. 2) (20). Indeed, apart from its receptor, sCD40L also binds to the glycoprotein (GP) IIb/IIIa platelet receptors, inducing their activation, and GP IIb/IIIa antagonists reduce sCD40L release from activated platelets in vitro (21). As we have recently shown, GPIa platelet receptor may also regulate sCD40L release from activated platelets (22). Carriers of the 807T polymorphism on the GPIa gene, which regulates surface density of the receptor, express higher sCD40L levels during the acute phase of myocardial infarction (22). Noticeably, healthy carriers of the 807T allele also express higher levels of sCD40L in the presence of endothelial injury (22). However, there is evidence that sCD40L may not directly promote atherogenesis (23), because previous studies in mice suggested that CD40L modulates atherogenesis primarily by its expression on nonhematopoietic cell types rather than monocytes, T lymphocytes, or platelets (23). Therefore, as circulating sCD40L is mainly derived from activated platelets, its association with atherothrombosis could be primarily due to its ability to reflect platelet activation and less because of a direct impact in atherothrombosis.
Finally, CD40L (and possibly sCD40L) play a key role in atherothrombosis by being a link between platelets, inflammation, thrombosis, and atherogenesis (18). The most important mechanisms by which the CD40/CD40L axis affects atherothrombosis are summarized in Figure 2.
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CD40L in Stable and ACS: Insights From Clinical Studies
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After the initial observations from basic science supporting that CD40L perpetuates inflammation and induces thrombus formation in experimental models (1), many studies have examined the potential role of CD40/CD40L interactions in ACS and stable coronary artery disease (CAD) at a clinical level. These studies have demonstrated that circulating sCD40L levels are significantly higher in patients with acute myocardial infarction (AMI) or unstable angina, compared with healthy persons (22,24–33) (Table 1). Indeed, it appears that a gradual increase in sCD40L levels takes place with ACS progression (26,28). Transcoronary sCD40L levels exhibit an early peak just 9 h after onset of AMI or unstable angina (27,34). However, there is no significant difference between AMI and unstable angina patients in circulating sCD40L levels (24). Interestingly, intracoronary CD40L levels are higher in the culprit coronary artery than in the peripheral circulation, reflecting the activation of a potent local inflammatory process (27,31,35).
As we have recently shown, sCD40L levels are independent from the underlying proinflammatory state in AMI or CAD patients, as assessed by circulating levels of IL-6, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 (24). Conversely, in healthy subjects, sCD40L is strongly associated with IL-6 serum levels (24). Therefore, it seems that in patients with AMI or CAD, circulating sCD40L may be dominantly dependent on sCD40L release from activated platelets and to a lesser extent on inflammatory status, which is a major determinant of sCD40L in healthy subjects (24). Although the clinical importance of circulating sCD40L in ACS is still controversial (28), it seems that measurement of sCD40L can be evaluated either as an inflammatory marker or as a marker of platelet activation, depending on the underlying disease state.
The vast majority of data regarding stable CAD are derived from clinical studies comparing the effect of CD40/CD40L interactions in ACS with the effect in stable CAD and healthy subjects. As we (24) have shown, plasma sCD40L is higher in patients with stable angina than in healthy subjects, but lower compared with patients with ACS (24). Indeed, multiplicity of risk factors is associated with a summing effect, leading to an even higher increase in sCD40L levels in CAD patients (24), although there is a wide variation between different clinical studies (Table 1) (29,36,37).
Circulating sCD40L levels in stable or unstable coronary syndromes are also affected by genetic determinants. Genetic polymorphism A3459G on sCD40L has been reported as a determinant of sCD40L levels, with carriers of 3459G allele having elevated sCD40L levels during ACS (30). We have previously demonstrated that genetic polymorphisms affecting the expression of GPIa on platelets' surface (such as C807T polymorphism on the GPIa gene) may affect sCD40L levels in clinical conditions such as stable CAD or AMI, whereas this effect is not observed in healthy persons, in whom platelet activation is not the driving force of circulating sCD40L (22).
Taken together, these complex mechanisms regulating circulating sCD40L levels in humans make the interpretation of this biomarker extremely difficult, limiting its clinical use.
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Methodological Considerations Regarding Measurement of sCD40L in Humans
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A number of methodological issues regarding the measurement of circulating sCD40L levels in humans may partly explain the controversial results provided by the various clinical studies. In more detail, a recent study reported that sample preparation may substantially influence sCD40L levels, suggesting that increased sCD40L levels may result from in vitro platelet activation (38). Therefore, it has been suggested that plasma samples are more suitable for sCD40L measurements because serum sCD40L levels are correlated with platelet count and reflect their in vitro activation status (36). Furthermore, whole blood should be assessed as soon as possible after blood sampling. Prolonged keeping (3 h) at room temperature before freezing may lead to a false increase in sCD40L levels, whereas temporary storage at 4°C has minimal effects on plasma sCD40L (39). Importantly, sCD40L levels appear to have diurnal variations (being elevated during the light phase compared with the dark phase) (40), indicating the need for standardizing time of blood sampling in clinical studies.
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CD40L and CAD Prognosis
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A growing body of evidence has shed light on many aspects of the role of CD40L in cardiovascular disease, and it has been supported that it may have a predictive value (41–46) (Table 2). In the Women's Health Study, high sCD40L plasma levels were associated with a higher risk of major cardiovascular events (47). In the CAPTURE (c7E3 Fab Anti-Platelet Therapy in Unstable Refractory Angina) trial (19), patients with high sCD40L levels had an almost 3-fold higher risk for cardiovascular death or AMI (19), whereas in the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) study, high sCD40L was an independent risk factor for recurrent cardiovascular events (19,48). Indeed, it has been suggested that combined assessment of CD40L and troponin-T levels has better predictive value regarding AMI risk (30). Moreover, carriers of the –3459A>G polymorphism in the CD40L gene are at higher AMI risk, indicative of a causal role of sCD40L in the pathophysiology of ACS (30). Notably, a small prospective study suggested that high sCD40L levels predict angiographic restenosis in patients who undergo coronary angioplasty (49). In contrast, other clinical studies suggested that CD40L has no predictive value in patients with CAD (50,51) or ACS (52,53) (Table 2).
In conclusion, given the lack of a standardized methodological approach and the complexity of CD40L pathophysiology, clinical studies have yielded contradictory results (Table 2). Therefore, additional large prospective trials are needed to clarify the possible predictive value of sCD40L in cardiovascular disease.
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CD40/CD40L as a Therapeutic Target in Atherosclerosis
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Antiplatelet/antithrombotic agents.
As activated platelets are the main source of circulating sCD40L, antiplatelet agents were among the first drugs studied for their CD40L-lowering properties. Clopidogrel, which acts via adenosine diphosphate receptor inhibition, completely inhibits sCD40L release from adenosine diphosphate-stimulated platelets; patients under clopidogrel treatment exhibit reduced CD40L platelet expression and circulating sCD40L levels (54). Moreover, it was also found that both short- and long-term treatment with clopidogrel significantly reduces sCD40L levels in patients with stable CAD (55), although a recent study demonstrated enhanced expression of CD40L on platelets surface after 1 year of treatment with clopidogrel 75 mg/day plus aspirin 325 mg/day in patients with CAD (56).
Cyclooxygenase-2 inhibition may also be a potential target. Patients receiving aspirin exhibit decreased sCD40L release from platelets after platelet activation with collagen (21). The GP IIb/IIIa receptor inhibitors, such as eptifibatide, abciximab, and tirofiban, inhibit platelet aggregation as well as sCD40L release in vitro (21). The beneficial effect of GP IIb/IIIa inhibitors has been also demonstrated in clinical studies. The GP IIb/IIIa antagonists appear to be particularly beneficial for the subgroup of high-risk ACS patients with increased sCD40L levels; abciximab significantly reduced cardiovascular risk in patients with elevated sCD40L levels in the CAPTURE trial (19). In addition, as increased sCD40L levels reflect a prothrombotic state, the FRISC II (Fragmin and fast Revascularization during InStability in Coronary artery disease II) study demonstrated that low-molecular-weight heparin (dalteparin) reduces the risk of AMI in non–ST-segment elevation ACS patients with high sCD40L levels (30,57).
Statins.
Multiple pleiotropic effects have been attributed to statins; recent in vitro studies have demonstrated that statins can also reduce oxidized low-density lipoprotein–induced or cytokine-induced CD40L expression on human umbilical vein ECs, SMCs, and mononuclear phagocytes in a concentration-dependent way (5). Additionally, incubation of activated platelets with atorvastatin leads to decreased platelet-induced cycloxygenase-2 expression in human umbilical vein ECs (58). Therefore, statins may be actively implicated in platelet-endothelium interaction. Indeed, at a clinical level, statin treatment reduces plasma sCD40L levels in patients with CAD (59). Notably, the MIRACL study (48) demonstrated that early atorvastatin treatment initiation after ACS reduces the risk for future cardiovascular events associated with high sCD40L levels; nevertheless, atorvastatin treatment only slightly affected sCD40L levels.
Thiazolidinediones.
Thiazolidinediones are peroxisome proliferator-activated receptor- agonists, widely used in type 2 diabetes mellitus treatment. Evidence from in vitro studies suggests that different cell types, such as platelets or ECs, treated with thiazolidinediones exhibit reduced expression of CD40L messenger ribonucleic acid or protein levels (60). Rosiglitazone treatment for 12 weeks significantly reduced serum sCD40L levels in patients with type 2 diabetes mellitus and CAD compared with placebo (61), although short-term rosiglitazone treatment failed to affect sCD40L levels in healthy persons (62), highlighting the complex mechanisms regulating sCD40L release in different disease states.
Other strategies.
Several studies have also investigated the sCD40L-lowering properties of various nutritional and pharmaceutical agents. Patients with AMI receiving n-3 fatty acids on a daily basis for 12 months had significantly reduced sCD40L levels (63). Additionally, in vitro data support a potent effect of antioxidants on CD40L expression, even though it is still unknown if this efficacy confers any clinical benefits. Specifically, CD40L expression is inhibited in activated platelets treated with antioxidants such as vitamin C, superoxide dismutase, or phospholipase A2 inhibitors (57). Other strategies such as angiotensin-converting enzyme inhibitors also reduce sCD40L levels in various subpopulations, as we have previously described (64). Finally, despite the stimulatory effect of homocysteine on sCD40L release, the effect of homocysteine-lowering treatment with folic acid on circulating sCD40L in CAD patients remains controversial (65).
Despite these important findings, the role of CD40/CD40L as a direct therapeutic target in atherothrombosis has been questioned, as both CD40L–/– mice (66) and humans receiving antibodies against CD40L (67) appear to have higher rates of thromboembolic complications, suggesting that inhibition of platelet CD40L may render platelet plugs unstable. Indeed, Langer et al. (66) have suggested that the interactions between CD40 and CD40L-immune complexes may derange platelet function and be responsible for the thromboembolic complications noted.
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Conclusions
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CD40L and its soluble counterpart, sCD40L, are molecules with prothrombotic and proinflammatory properties, expressed in a variety of tissues such as immunity cells, vascular wall, and most importantly, platelets. Multiple autocrine, paracrine, and endocrine effects have been attributed to CD40/CD40L, triggering all together atherothrombosis. Patients with both stable and unstable coronary artery disease exhibit higher circulating sCD40L levels, and it is likely that sCD40L may have a predictive value. However, a number of questions need to be resolved in this area of research in the coming years. The protocols measuring serum or plasma sCD40L need to be standardized in clinical practice, as technical issues may explain the huge variation of the findings across the literature. Importantly, evidence suggests that reducing high sCD40L levels by the use of conventional drugs such as antiplatelet agents and statins may lead to improved clinical outcome. However, it is still unclear whether sCD40L can be used as a therapeutic target in cardiovascular disease, as circulating sCD40L levels reflect mainly platelet activation, and the direct involvement of sCD40L (as opposed to membrane-bound CD40L) in atherogenesis has been questioned. Therefore, more clinical studies in different cohorts, using standardized methods for measuring sCD40L, are required to elucidate these issues.
Although the development of therapeutic strategies specifically targeting CD40/CD40L seems promising, the use of antibodies against CD40L has been associated with thromboembolic events, and these data have weakened the enthusiasm for future studies using CD40L/CD40 as a direct therapeutic target in atherosclerosis. Upcoming results of long-awaited large clinical trials would hopefully elucidate the potential use of CD40L (and/or sCD40L) as a reliable biomarker and therapeutic target in cardiovascular disease.
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Footnotes
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Dr. Antoniades is supported by a reintegration grant within the 7th European Community Framework Programme.
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Abstract
Structure of CD40/CD40L and...