doi: 10.1161/hh2401.101272
© 2001 American Heart Association, Inc.
Reviews |
CD40 Signaling and Plaque Instability
From the Leducq Center for Cardiovascular Research, Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Uwe Schönbeck, Leducq Center for Cardiovascular Research, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 309, Boston, MA 02115. E-mail uschoenbeck{at}rics.bwh.harvard.edu
Abstract
Today, multiple lines of evidence support the view of atherosclerosis as a chronic inflammatory disease and implicate components of the immune system in atherogenesis. Recent work has documented overexpression of the potent immune mediator CD40 and its counterpart CD40 ligand (CD40L) in experimental and human atherosclerotic lesions. Notably, interruption of CD40/CD40L interactions not only diminished the formation and progression of mouse atheroma, but also fostered changes in lesion biology and structure, which are associated in humans with "plaque stabilization." In accordance with the hypothesis that CD40 signaling promotes plaque instability, in vitro studies demonstrated that ligation of CD40 on atheroma-associated cell types, namely endothelial cells, smooth muscle cells, and macrophages, mediates functions considered crucial to the process of atherogenesis, such as the expression of cytokines, chemokines, growth factors, matrix metalloproteinases, and procoagulants. The combination of the broad gamut of proatherogenic biological responses triggered by ligation of CD40 on endothelial cells, smooth muscle cells, and macrophages in vitro and the results of in vivo studies of interruption of CD40 signaling suggests a central role for this receptor/ligand dyad during atherogenesis, proposing CD40/CD40L interactions as a novel potential therapeutic target for this prevalent human disease.
Key Words: CD40 • CD40L • atherosclerosis • inflammation • immunity
Concepts of the pathogenic mechanisms of atherosclerosis have recently undergone considerable evolution. We have learned to appreciate that atherosclerotic complications commonly involve nonstenotic lesions, sharpening our focus on plaque biology rather than hydraulics.1 Accordingly, the view of atheroma as mere accumulation of plasma lipoproteins progressively producing luminal occlusion has given way to an understanding of atherosclerosis as a chronic inflammatory disease in which both lipid and inflammatory pathways intertwine in a complex network.2,3 Several decades ago, evidence surfaced associating inflammatory cells with atherogenesis, namely the accumulation of mononuclear phagocytes in early as well as complex atherosclerotic lesions. Yet, the involvement of cellular immunity in this prevalent human disease emerged only recently. In the mid-1980s, G.K. Hansson’s group demonstrated that T lymphocytes constitute a prominent cell type in atheroma.4 These mostly CD4+ T lymphocytes represent a polyclonal population of chronically activated cells in late-stage lesions.4–6 Despite the appreciation that atherogenesis involves immunocompetent cells, the mediators and mechanisms that evoke the chronic inflammatory processes implicated in plaque formation and progression, and that eventually trigger the acute clinical complications, remain incompletely defined.
Initial work on the receptor CD40 and its counterpart CD40 ligand (CD40L, recently renamed CD154) considered their expression to be limited to B lymphocytes and CD4+ T lymphocytes, respectively.7–11 Accordingly, functional studies focused on the role of CD40 signaling in T/B lymphocyte interactions, mediating T cell–dependent B-cell activation and differentiation required for mature humoral immune responses. Indeed, defective interactions between CD40 and its ligand, as caused by genetic mutations in either partner, precipitated severe immunodeficiencies in animal models and in humans, such as the X-linked hyper-IgM syndrome.10,11 More recent studies, however, challenged the view of the CD40/CD40L dyad as a mere lymphocytic cofactor functioning solely in thymus-dependent humoral immune responses. We now understand that a variety of leukocytic cells, but also nonleukocytes, express both CD40 and CD40L (Table 1). Furthermore, ligation of CD40 regulates a wide gamut of biological functions in vitro and in vivo, extending beyond cellular immunity to inflammation in the broadest sense, two processes intimately involved in atherogenesis.
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Expression of CD40 and CD40L in Human Atheroma–Associated Cells
The identification of the T lymphocyte as the original source of CD40L in 1992,12–14 together with the presence of chronically activated CD4+ T lymphocytes in human atheroma,4–6 set the stage for a possible involvement of this immune mediator in atherogenesis. Only a year later, Cocks et al15 demonstrated expression of CD40L transcripts by cultured macrophages (M
). Furthermore, Alderson et al16 showed that the constitutive expression of CD40 protein by this cell type increases in responses to the proinflammatory mediators granulocyte/M colony-stimulating factor (GM-CSF) and interferon (IFN)-
, molecules overexpressed in human atheroma.2,3 In 1995, three groups independently reported the expression of functional CD40 on endothelial cells (ECs).17–19 Cultured ECs as well as endothelium of nondiseased vascular tissue expressed this receptor constitutively. Stimulation with interleukin (IL)-1, tumor necrosis factor (TNF)-
, and particularly IFN-, proinflammatory cytokines abundant within atheroma,2,3,20 enhanced the expression of endothelial CD40 in vitro. Accordingly, endothelium in vessels of inflamed skin tissue showed enhanced CD40 expression in situ.17
In 1997 we reported colocalization of both CD40 and CD40L on atheroma-associated ECs, smooth muscle cells (SMCs), and M in vitro and in situ (Figure 1).21 Moreover, T lymphocytes within human atherosclerotic lesions also expressed CD40L. Although it was originally discussed controversially, several groups have subsequently confirmed the expression of CD40L on nonlymphocytic cell types (Table 1).22–27 Both receptor and ligand, expressed on cultured ECs, SMCs, and M, are functional, mediating the various proatherogenic processes outlined below (Table 2). In additional studies, our group demonstrated expression of CD40 and CD40L in atheromatous tissue of hypercholesterolemic mice with a staining pattern similar to that observed in humans.28 Most recently, platelets were added to the list of sources of CD40L. These cells release presynthesized, stored functional ligand within seconds of activation in vitro and during thrombus formation in vivo.29
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The In Vivo Role of CD40/CD40L in Atherogenesis
Given the prominence of CD40 and CD40L in human and experimental atheroma, we sought direct in vivo evidence that interruption of CD40 signaling modifies this disease. Indeed, treatment with anti-mouse CD40L antibody limited atherosclerosis in LDL receptor–deficient mice consuming a high-cholesterol diet for 12 weeks, significantly reducing the size and lipid content of aortic atherosclerotic lesions.28 Furthermore, atheroma of mice treated with anti-CD40L contained markedly fewer M and T lymphocytes, and showed reduced expression of adhesion molecules and matrix metalloproteinases (MMP) compared with controls.28,30 Studies using CD40L/low-density lipoprotein receptor (Ldlr) (U.S., unpublished data, 2000) or CD40L/apolipoprotein E (ApoE) double-deficient mutant mice31 confirmed the crucial role for CD40 signaling during the initiation and progression of atherosclerotic lesions in two different mouse strains.
These findings provided not only new evidence for the importance of inflammatory pathways in atheroma formation in response to elevated LDL, but further pointed to CD40/CD40L interactions as a potential therapeutic target. However, continuous interruption of the CD40/CD40L pathway from early age on probably does not provide an attractive therapeutic strategy. We therefore tested whether interruption of CD40 signaling could retard the progression or even regress established atherosclerotic lesions in vivo. Interestingly, anti-CD40L antibody treatment of Ldlr-deficient mice during the second half of a 26-week regimen of high-cholesterol diet did not cause regression, but abrogated the progression of established atherosclerotic plaques, as determined by lesion size.32 Of particular note, however, interruption of CD40 signaling altered the composition of atheroma. The antibody treatment yielded decreasing content of proatherogenic players such as M, lipids, and inflammatory cytokines, but elevated relative content of SMCs and fibrillar collagen, the major load-bearing molecule within the fibrous cap of the plaque. Similar morphological changes have been reported in ApoE-deficient mice,33 demonstrating that interruption of CD40 signaling improves plaque stability independent of a certain mouse strain.
Combined, these studies revealed that ligation of CD40 on atheroma-associated cells prominently promotes atherogenesis and that interruption of CD40/CD40L interactions in mice fosters features of atherosclerotic plaques associated with stability in humans.
Potential Atherogenic Functions of CD40/CD40L Interactions
The modulation of plaque characteristics toward those of stable, less rupture-prone lesions by interruption of CD40/CD40L interactions in vivo agrees well with the proatherogenic processes triggered by CD40 ligation in atheroma-associated cells in vitro. In the following, we will consider these effects of CD40 ligation in three sections: the initiation, progression, and acute complications of atherosclerotic lesions (Figures 2A through 2C). Although this approach oversimplifies this complex disease, it illustrates how CD40 signaling can impact atherosclerosis at all stages.
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Initiation of Atherosclerotic Lesion Formation
The initial trigger of CD40 and CD40L expression within T lymphocytes, M, ECs, and SMCs of developing human atherosclerotic lesions remains uncertain. However, candidates involve modified lipoproteins, eg, oxidized LDL, pathogens such as Chlamydia pneumonia, disturbed mechanical forces, or heat shock proteins (Figures 2A and 3A). In support of this hypothesis, a recent study colocalized lesional CD40 and CD40L with epitopes characteristic of oxidized LDL.25 Moreover, we recently demonstrated that lipid lowering limits the expression of CD40L in experimental atheroma.34 Presentation of antigen to T lymphocytes might provide another early pathway initiating the expression of CD40L.35 In addition, CD40L can enhance its own expression as well as that of its receptor.36 Finally, IFN-, a cytokine expressed early during atherogenesis, potently induces CD40/CD40L expression.7–11 Interestingly, contact with ECs stabilizes CD40L transcripts in T lymphocytes via lymphocyte function–associated antigen (LFA)–3/CD2 interactions, probably enhancing early CD40L protein expression on newly activated CD4+ T lymphocytes (Figure 2A).37
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Adhesion of Immunocompetent Cells
Enhanced adhesion of immunocompetent cells to the endothelium may be among the earliest proatherogenic functions mediated by the CD40/CD40L dyad. Ligation of CD40 on ECs and SMCs induces the expression of leukocyte adhesion molecules such as vascular cell adhesion molecule (VCAM)-1, E-selectin, and intercellular adhesion molecule (ICAM)-1,17–19,27 whereas CD40 ligation on M triggers LFA-1 and ICAM-1 expression (Table 2 and Figure 2A). 38 Notably, stimulation with CD40L enhanced the adhesion of T lymphocytes to cultured ECs, but diminished that of neutrophils, a cell type not commonly detected within undisrupted human atheroma.39 The importance of adhesion molecules in atherogenesis has been demonstrated in experimental models in which deficiency in CD40L-inducible adhesion molecules such as ICAM-1, VCAM-1, or P/E-selectin not only significantly diminished adhesion of immunocompetent cells, but also reduced the size of atherosclerotic lesions in ApoE-deficient mice.40–42
T Helper 1 (Th1) Immune Response
In addition to leukocyte adhesion, CD40/CD40L interactions, probably in combination with IFN-, foster a Th1 immune response, predominant at sites of atherosclerosis.20 Indeed, CD40 signaling appears to suffice for the induction of Th1-dominated, and the suppression of Th2-dominated, immune responses in vitro and in vivo.35 This function might involve suppression of IL-4 and induction of IL-12p40 expression by ECs, SMCs, and M (Table 2). 43,44 IL-12p40, dimerized with the IL-12p35 subunit, triggers synthesis of IFN-, a cytokine that not only directly promotes Th1 responses, but further elevates CD40 levels, suggesting a possible positive feedback loop.
Ligation of CD40 on atheroma-associated cells might also induce the expression of IL-15 (Table 2), as shown previously for epithelial cells and myoblasts.45–47 IL-15, overexpressed in experimental and human atheroma,48 is a potent stimulator of T-lymphocyte proliferation and synergizes with IL-12 in the production of IFN-, probably via the enhanced expression of CD40 on monocytes and of IL-12 receptor on T lymphocytes, thus accentuating Th1-predominant immune responses.49,50 Notably, IL-15 increases the expression of CD40L on T lymphocytes, illustrating yet another possible positive feedback loop that may operate in atherogenesis.51,52 Moreover, IL-15 may participate in the CD40L-mediated induction of IL-1ß synthesis in M.53 Of note, CD40/CD40L interactions augment the expression of active IL-1ß, a proinflammatory cytokine abundantly expressed in human atheroma, by several pathways. Ligation of CD40 on SMCs and M not only induces expression of the precursor of this cytokine, but also enhances the formation of active IL-1ß–converting enzyme (caspase-1) required for maturation of the inactive IL-1ß precursor.54,55 Of note, ligation of CD40 induced markedly lower levels of the IL-1 receptor antagonist, an endogenous inhibitor, from Th1 than from Th2 cells.53 In contrast to the induction of Th1 cytokines, ligation of CD40 suppresses Th2-mediated responses, probably by diminishing expression of IL-4 and IL-10 receptor (Table 2), two typical Th2 pathways, the activation of which limits expression of IL-12 and CD40.35,56
In sum, these data suggest that CD40/CD40L interaction triggers and/or supports a predominantly Th1 cytokine–driven inflammation through several pathways, thus establishing the immune reaction characteristic for atherogenesis (Figure 2A). The recent implication of CD40/CD40L interactions in the generation of type 1 cytokine responses in human leprosy supports this conclusion.57
Chemoattraction
Ligation of CD40 on ECs, SMCs, M, and T lymphocytes triggers expression and release of chemoattractants overexpressed within human atheroma, such as IL-8, MIP-1 (M inflammatory protein), MIP-1ß, RANTES (regulated on activation, normal T cell expressed and secreted), SDF-1 (stromal cell–derived factor 1), and MCP (monocyte chemotactic protein)-1 (Table 2 and Figure 2A).58–62 These chemokines probably attract and direct T lymphocytes and M to the atheroma, thus sustaining chronic inflammation. The importance of chemokine signaling for the accumulation of T lymphocytes within sites of chronic inflammation was supported by the in vivo location of SDF-1 and its receptor CXCR-4 (modulated by CD40 signaling) in human rheumatoid synovium.61 Furthermore, deficiency of chemokine receptors not only associates with diminished migration of immunocompetent cells, but also limits Th1-mediated immune responses, likely mediated by impaired IFN- expression.63 These processes could be associated with diminished expression of CD40, because IFN- provides a potent inducer of CD40 in human atheroma. In accordance with the postulated crucial role for chemokine signaling in atherogenesis, we and others demonstrated that lack of chemoattractants (eg, MCP-1), or their receptors (eg, C-C chemokine receptor [CCR]-2), significantly diminishes atherosclerotic lesion progression in mice.64,65
In summary, accumulating evidence illustrates how CD40/CD40L interactions can mediate several of the processes considered crucial in the initiation of atherosclerotic plaque formation, such as the expression of adhesion molecules and chemokines as well as the priming of a predominant Th1 cytokine–mediated immune response (Figure 2A). The recent finding that the most prominent elevation in the relative content of CD40-expressing M and SMCs within human atheroma occurs during the initial formation of the lesion supports this hypothesis,26 although several of these processes probably persist beyond the initial stage.
Progression of Atherosclerotic Plaques
The progression of atherosclerotic plaques toward differentiated, complex lesions commonly involves the migration and proliferation of SMCs, eventually yielding the fibrous cap overlying a lipid-enriched necrotic core, as well as the formation of neovessels, which support the growth of the lesion (Figure 2B).
Chemokines
The expression of chemokine receptors extends beyond hematopoietic cells, given that both ECs and SMCs express functional CCR-1 (receptor for MIP-1 and RANTES), CCR-2 (receptor for MCP-1), CCR-5 (receptor for MIP-1/ß as well as RANTES), and CXCR-4 (receptor for SDF-1).66–68 Although ligation of CD40 triggers expression of the respective chemotactic agonists, involvement of the receptor/ligand dyad in the formation of the SMC-enriched fibrous cap remains undetermined as yet (Figure 2C). Of note, however, MCP-1 promotes replication of SMCs and modulates the cell phenotype in vitro.69 Moreover, ligation of chemokine receptors triggers more than mere chemotactic activity, eg, the expression of tissue factor in SMCs and M.59,68–70
Angiogenesis
Several groups proposed that CD40L-induced pathways stimulate neovessel formation. In 1997, we demonstrated endothelial expression of CD40 within the neovascularized areas of atherosclerotic lesions,21 a finding recently confirmed.71 Accordingly, activation of ECs in vitro by interaction with CD40L induced the synthesis and release of various MMP, thereby promoting tubule-like structure formation.72 Recently, in vivo evidence was provided that CD40 ligation on ECs can mediate angiogenesis probably via expression of vascular endothelial growth factor (VEGF).73 CD40L-induced angiogenesis might further involve IL-1574 and cyclooxygenase-2 (Cox-2). We previously demonstrated that ligation of CD40 induced the expression of Cox-2 in cultured ECs, SMCs, and M, and that human atheroma showed particularly intense staining for Cox-2 in microvascular endothelium.75 More recent studies revealed that Cox-2 enhances basic fibroblast growth factor–induced angiogenesis through induction of VEGF76 and participates in VEGF-mediated angiogenesis.77,78 Finally, recent studies suggest a prominent role of another CD40L-inducible chemokine, IL-8, in angiogenesis.79
In sum, CD40/CD40L interactions modulate several of the processes considered crucial in the progression of atherosclerotic lesions beyond the stage of the fatty streak (Figure 2B). In support of a central role of the receptor/ligand dyad in this stage of atherogenesis, intimal thickness of human lesions significantly correlates with the expression of CD40 on atheroma-associated cells in situ.26 Continuous attraction of inflammatory cells, propagation of a predominant Th1-mediated immune response, induction of proliferative/mitogenic responses of SMCs, and promotion of lesion growth via angiogenesis might figure among the most prominent CD40L-mediated processes contributing to the progression of atherosclerotic lesions toward the vulnerable, rupture-prone plaque. Although direct evidence is absent, lack of progression of established lesions by anti-CD40L antibody treatment in mice supports the potentially eminent role of CD40/CD40L interactions in this stage of atherogenesis.32,33
Plaque Vulnerability and Clinical Complications
The genesis of "stable" atheromatous lesions (characterized by a thick fibrous cap containing significant intact fibrillar collagen and a small necrotic core) and of "vulnerable," rupture-prone lesions (characterized by a thin fibrous cap, paucity of collagen fibrils, and a large necrotic core) remain uncertain. Because, however, loss of interstitial collagen (the major load-bearing extracellular matrix component of the atherosclerotic plaque), relative lack of SMCs, and accumulation of procoagulant material characterize lesions that have disrupted and caused fatal thrombosis (Figure 2C), we will focus in the following on the potential involvement of CD40/CD40L interactions in these processes.
Degradation of Extracellular Matrix
Members of the MMP family participate in various processes of atherogenesis, such as angiogenesis, arterial remodeling, and thinning of the collagenous cap of the plaque.80 Loss of fibrillar collagen within the fibrous cap is probably mediated by a specialized MMP subfamily, termed interstitial collagenases. We have reported the expression of all three known interstitial collagenases, MMP-1, MMP-8, and MMP-13, in ECs, SMCs, and M within human and experimental atherosclerosis and colocalized degraded type I collagen with these MMP.81,82 Of note, both CD40 and CD40L localized with all three interstitial collagenases within human atheroma. Accordingly, ligation of CD40 on human vascular ECs, SMCs, and M in vitro induced not only expression of interstitial collagenases, but rather a full complement of MMPs (Table 2).11 In accordance with the hypothesis that CD40/CD40L interaction contributes to the loss of extracellular matrix in atherosclerotic lesions, interruption of CD40 signaling significantly enhanced the lesional content of collagen in mouse atheroma, as outlined above.32,33
Formation of the Necrotic Core
A possible role for CD40L in the formation of the necrotic core, a process involving both apoptosis and oncosis, remains to be determined. Previous reports, mostly using B lymphocytes, implicated CD40 signaling in both pro- and antiapoptotic pathways.11 As an example for this controversy, ligation of CD40 rescues M from cell death in vitro, but induces expression of proapoptotic Fas as well.83,84 Although implications of CD40 signaling in lesional apoptotic processes appear likely, our knowledge regarding the implications for the formation of the necrotic core in vivo remains rudimentary and will require further study.
Enhanced Procoagulant Activity
Several in vitro and in vivo studies suggest a central role for CD40/CD40L interactions in the regulation of the thrombotic potential of the atheroma. Ligation of CD40 on ECs, SMCs, and M potently induced the expression of procoagulant tissue factor in vitro.85–90 Diminished expression of thrombomodulin, the "anticoagulant" receptor for thrombin by CD40 ligation, further supported an eminent role for CD40/CD40L interactions in the determination of the procoagulant status of a cell.88,89 Moreover, in experimental models, expression of this receptor/ligand dyad correlates with tissue factor content in vivo.34 Although the established biological function of this molecule depends on the extracellular domain, a critical initiator of blood coagulation,91 recent studies suggested the involvement of the intracellular tissue factor domain in additional proatherogenic functions such as apoptosis, production of growth factors, and SMC migration.92–94
In summary, CD40/CD40L interactions mediate several of the processes that set the stage for plaque rupture and its clinical sequelae (Figure 2C). Unfortunately, no experimental model of plaque rupture is available to directly test the relevance of CD40/CD40L interactions in these final steps of atherogenesis. However, studies from our own group (U.S., unpublished observations, 1999) and others95 demonstrated that patients with unstable angina have enhanced plasma concentrations of soluble CD40L (sCD40L). Nevertheless, it remained unknown whether circulating sCD40L represents a marker or consequence of cardiovascular disease, as elevations in sCD40L concentrations in this particular patient population could result secondarily from a clinical event (eg, release of sCD40L from platelets after thrombus formation), rendering elevated plasma sCD40L concentrations an "innocent" bystander at this stage of the disease process. Alternatively, enhanced sCD40L concentrations might result from subclinical thrombotic events and repeated healing sequences, eventually yielding ligand concentrations sufficient to exacerbate clinical symptoms. A recent study from our group indeed supports the hypothesis that sCD40L might provide a novel prognostic marker/mediator, because high plasma concentrations of sCD40L correlate with increased cardiovascular risk in apparently healthy women.96
Therapeutic Implications for Interruption of CD40/CD40L in Atherogenesis
The finding that interruption of CD40/CD40L interactions fosters features of atherosclerotic plaques associated with stability in humans raises the potential of manipulation of this receptor/ligand dyad as a therapeutic tool. Notably, CD40/CD40L inhibition has also been pursued as a therapeutic tool in other chronic inflammatory diseases, including multiple sclerosis, lupus nephritis, collagen-induced arthritis, spontaneous autoimmune diabetes, inflammatory bowel disease, and cancer. Like atherosclerosis, these diseases exhibit elevated expression of CD40L, locally within the inflamed tissue and/or systemic within the serum of affected patients. Indeed, interruption of CD40/CD40L interaction appeared to be the therapeutic target of choice, given that in vivo studies demonstrated that administration of anti-CD40L antibodies to animals affected with experimental diseases improved outcomes. Continuous and/or systemic treatment, however, might not provide a clinically attractive therapy for atherosclerosis, a disease that commonly develops over decades. And although it remains controversial whether short-term interruption of the "inflammatory cycle" might suffice to mediate long-term benefits in atherosclerosis, recent studies support this latter treatment strategy for other diseases. Single application of a humanized monoclonal antibody against CD40L provided long-term protection against acute renal allograft rejection.97 Accordingly, studies analyzing the safety and pharmacology of humanized anti-CD40L antibodies have been initiated. Although initial reports showed enhanced thromboembolic complications when applied to a different disease (systemic lupus erythematosus), more recent studies demonstrated that single intravenous administration of a different humanized anti-CD40L antibody proved safe and well tolerated in a similar population.98 However, long-term observations will be required to appropriately judge the risks and benefits of such treatment.
Moreover, the ability of CD40L to mediate and/or prevent apoptosis has stimulated interest in this molecule as a therapeutic target in cancer treatment. Interestingly, two opposing strategies have emerged, one aimed at inhibiting CD40/CD40L interactions to diminish the mitogenic potential of CD40L on lymphoma or other cancer cells. The other either applies exogenous CD40L or enhances the endogenous expression of the ligand to trigger cell death.10,11
The outcome of ongoing as well as future clinical studies will demonstrate whether the current strategies of systemic manipulation of this mediator of humoral and cellular immune responses might indeed prove beneficial in the clinical setting of certain diseases. With respect to the potential treatment of atherosclerosis, however, these strategies must overcome several hurdles, because the current determination of an individual with enhanced future cardiovascular risk is limited and the disease progresses over the duration of decades, probably starting in early adolescence. Long-term interruption of CD40/CD40L interaction for prolonged periods of time will likely trigger severe immune deficiencies in individuals of (thus far) unpredictable risk to experience cardiovascular complications triggered by plaque rupture. Hence the importance of more detailed studies regarding the molecular mechanisms underlying the proatherogenic actions of CD40L. Utilization of different signal transduction pathways in distinct atheroma-associated cell types could provide more specific therapeutic targets, obviating potential undesired effects of global interruption of CD40 signaling. Therefore, we will review below the biochemical characteristics of the receptor/ligand dyad as well as CD40 signal transduction pathways.
Pathways of CD40 Signaling
CD40
CD40 belongs to the TNF receptor (TNFR) superfamily that also includes TNFR type I (p55-TNFR, CD120a) and type II (p75-TNFR, CD120b), low-affinity nerve growth factor receptor, CD27, CD30, CD95 (Fas/Apo), Ox40, DR-3/4/5, RANK, and 4-1BB.99 Transcription of the gene yields a 48-kDa type I transmembrane protein that comprises 277 amino acids. Gene transcription probably occurs via activation of nuclear factor (NF)-
B and STAT binding sites within the promoter region.11,22 Accordingly, recent studies demonstrated directly involvement of RelB in the expression of CD40.100 At the amino acid level, human and murine CD40 share 62% overall sequence similarity, with the intracellular domain and the C-terminal 32 residues achieving 78% and 100% identity, respectively. Three-dimensional models of the extracellular region of CD40 indicated strong structural homologies to the TNFR.101
Beyond the originally described source, the B lymphocyte, many cells can express CD40, including those implicated in atherogenesis, namely ECs, SMCs, and M (Table 1).7–11 These cells commonly express the receptor constitutively in vitro and show basal expression in nondiseased tissue. Stimulation with inflammatory cytokines, eg, IL-1, IL-3, TNF-, GM-CSF, and particularly IFN-, enhances expression of CD40 in vitro.7–11
CD40L
CD40 ligand (recently renamed CD154) is a member of the TNF gene superfamily, consisting of molecules such as TNF-, CD27 ligand, CD30 ligand, Fas ligand, lymphotoxin /ß, APRIL, RANK ligand, Ox40 ligand, and TRAIL.99 Cloning of human CD40L from activated peripheral blood T lymphocytes using the respective murine probe12–14 revealed a 13-kb DNA sequence, which shared 80% sequence similarity with its murine counterpart.102 Transcription of the CD40L gene yields a 2.3-kb mRNA, encoding a 261-amino acid–containing type II transmembrane protein.10,11 In addition to the cell-associated full-length 39-kDa protein, functional smaller soluble forms of the ligand arise through unknown mechanisms.103,104
Beyond the original source, activated CD4+ T lymphocytes, numerous cell types can express CD40L, including those implicated in atherogenesis, namely ECs, SMCs, M, and platelets (Table 1).7–11 In contrast to CD40, quiescent cultured cells and nondiseased tissue typically do not express the ligand constitutively. In addition to signaling through the T-cell receptor for antigens, proinflammatory cytokines, such as IL-1, IL-12, TNF-, or IFN-, as well as glucocorticoids, induce expression of the ligand in T lymphocytes, probably by activating the transcription factors activator protein-1 (AP-1) and nuclear factor of activated T cells (NF-AT).11,21,102,105–109 Of note, CD40L may induce its own expression.36
CD40 Signaling
In contrast to the expression of CD40 and CD40L, signal transduction pathways triggered by this interaction appear to differ significantly within certain cell types and at various stages of activation and differentiation.110 Such distinct CD40 signaling pathways may provide novel therapeutic targets allowing for a more defined approach in the treatment of inflammatory diseases. Unfortunately, to date, little information exists regarding CD40 signaling pathways in ECs, SMCs, or M. Therefore the following paragraph will focus on information obtained in B lymphocytes and correlate this information with that obtained in atheroma-associated cells.
As with other members of the TNFR superfamily, effective activation of the CD40 signaling pathway requires multimerization of the receptor.99,111 Originally, trimerization of the receptor was thought to depend on the association of the trimeric ligand (Figure 3A). More recent studies, however, suggested that CD40 could homotypically associate via conserved pre–ligand binding assembly domains that mediate ligand-independent assembly of functional receptor trimers.112 Thus, CD40 might be expressed on the cell surface as a preformed complex rather than monomeric receptor subunit, requiring binding of trimerized ligand to trigger CD40 signaling pathways (Figure 3B).112 In accordance with this model, trimeric recombinant CD40L possessed much greater activity than the monomeric ligand.113 Cell type–specific regulation of CD40 signaling might be further mediated by distinct endogenous control mechanisms. Alternative splicing of the CD40 mRNA, probably designed to prevent extensive (chronic) activation of this signaling pathway, might provide such a mechanism. Transcripts generated within the early stages of activation yielded functional CD40, whereas M expressed predominantly nontranslatable CD40 mRNA splice variants at later stages.114 Demonstration of whether dysregulation of such control mechanisms in distinct cell types might modulate inflammation in atheroma, however, requires further study.
The cytoplasmic region of CD40 bears two major signaling domains.115,116 Accumulating evidence suggests that CD40 signaling requires the association of either or both domains with binding proteins termed TNFR-associated factors (TRAFs).10,11 The TRAF family consists of six known members, of which TRAF1, TRAF2, TRAF3, and TRAF6 directly, and TRAF5 probably via TRAF3/TRAF5 hetero-oligomers, associate with CD40 (Figure 3C).10,11 Overexpression of TRAF2, a TRAF3 splice variant, TRAF5, and TRAF6 in B lymphocytes activates stress-activated protein kinases (SAPK) and NF-B. Stability of TRAF3 may regulate the CD40-mediated activation of NF-B, suggesting proteolysis of TRAF3 as a requirement for the CD40-mediated activation of this transcription factor.117 In addition, binding of TRAF6 activates the extracellular signal–regulated kinases (ERK) 1 and 2 as well as p38 mitogen-activated protein kinase (MAPK),11,118–125 leading to recruitment of NF-B–inducing kinase (NIK), which in turn can activate NF-B, probably via IB-kinase I/II (IKK-I/IKK-II) (Figure 3D).126 TRAF2 and TRAF6 can further activate the c-Jun N-terminal kinase (JNK) signaling pathway. In sum, CD40 ligation (in B lymphocytes) triggers the activation of all three known MAPK signaling pathways and eventually of the transcription factors NF-B, AP-1, and NF-AT (Figure 3E), which affects most of the proatherogenic mediators outlined above.
Interestingly, also within ECs, CD40 ligation induced activation of NF-B, interferon regulatory factor-1 (IRF-1), ATF-2/c-Jun, and JNK,127 and CD40-mediated signaling events in SMCs include tyrosine phosphorylation as well as activation of NF-B (Figure 3E). 128 In monocytes, ligation of CD40 enhances the constitutive expression of TRAF5 and triggers activation of MEK1 and MEK2 and their substrates ERK1 and ERK2, as well as of the JNK pathway (Figure 3E).129 These data agree with previous observations in this cell type, demonstrating that CD40 ligation activated MAPK, its substrate MAPKAPK-2, and the c-Jun N-terminal kinase.130,131 Additional studies implicated the Src tyrosine kinase Lyn in monocytic CD40 signaling pathways.132,133 Of note, with respect to potential therapeutic approaches, monocytes show distinct features in the CD40 signaling pathways used; ie, ligation of CD40 on M triggers activation of p50 homodimeric NF-B complexes, whereas the transcription factor complex in B lymphocytes comprises p50/p65 heterodimers. Moreover, although the Janus kinase-3 tyrosine kinase associates with CD40 in both monocytes and B lymphocytes, phosphorylation is only observed in CD40L-stimulated monocytes, with subsequent induction of STAT5 DNA binding activity.134 These findings support the hypothesis that cell type and activation status determine distinct CD40 signaling pathways, which eventually might result in the identification of therapeutic targets allowing intervention of CD40 signaling in the atheroma-relevant context only. This hypothesis is further supported by immunohistochemical in situ studies demonstrating differential expression of TRAF2 and TRAF3 within various human tissue.135
Finally, CD40-induced TRAF-mediated signaling is probably regulated via interaction of TRAF family members with I-TRAF, which inhibits TRAF2-mediated NF-B activation, probably by maintaining TRAFs in a latent state (Figure 3D).136 Interestingly, I-TRAF is a substrate of inducible IB kinase (IKK-I), and NF-B activation by IKK-I probably results from phosphorylation of I-TRAF by IKK-I and subsequent liberation of TRAF2 (Figure 3D).137 However, whether I-TRAF provides another therapeutic target remains unclear, because expression in atheroma-associated cells has not been investigated yet.
Conclusion
Research during the last decade has identified a plethora of inflammatory mediators potentially involved in atherogenesis. As evidence favoring involvement of many of these proinflammatory cytokines has accumulated in vitro and in vivo, the question arises whether the CD40/CD40L dyad just adds to the growing list of mediators implicated in this disease. Notably, however, at least two features discussed here suggest a particularly prominent role for CD40/CD40L interactions in atherogenesis. First, CD40 signaling can promote the expression of proatherogenic mediators regulated poorly if at all by other cytokines such as IL-1, TNF-, or IFN-. Examples include certain MMPs, caspase-1, and procoagulant activity. Second, CD40L promotes the expression of a broad array of proatherogenic mediators and may thus occupy a proximal position in the cytokine cascade implicated in atheroma progression. The spectrum of functions of CD40 ligation span the gamut from very early atherogenesis through the late acute thromboembolic complications of this disease. The ability of CD40L to elicit inflammatory programs in all major cells implicated in atherosclerosis underscores its potentially central role in this disease. In sum, the studies reviewed here point to the need for further investigations of the intricate interplay of CD40 and CD40L in the pathophysiology of atherosclerosis. Such studies might lead to insights into novel therapies for this prevalent disease.
Acknowledgments
This work was supported by grants from the National Heart, Lung, and Blood Institute (Grants HL-34636 and HL-56985, to P.L.). We apologize for not citing a more complete list of original references because of space restrictions, and we refer readers to the respective reviews cited here for more detail.
Received May 10, 2001; revision received October 22, 2001; accepted October 23, 2001.
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H. S. Lim, A. D. Blann, and G. Y.H. Lip Soluble CD40 Ligand, Soluble P-Selectin, Interleukin-6, and Tissue Factor in Diabetes Mellitus: Relationships to Cardiovascular Disease and Risk Factor Intervention Circulation, June 1, 2004; 109(21): 2524 - 2528. [Abstract] [Full Text] [PDF]
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U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]
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 G. Targher and G. Zoppini Soluble CD40L in Young Type 1 Diabetic Individuals Without Clinical Microvascular and Macrovascular Complications Diabetes Care, May 1, 2004; 27(5): 1236 - 1237. [Full Text] [PDF]
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A. H. Wagner, B. Guldenzoph, B. Lienenluke, and M. Hecker CD154/CD40-Mediated Expression of CD154 in Endothelial Cells: Consequences for Endothelial Cell-Monocyte Interaction Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 715 - 720. [Abstract] [Full Text] [PDF]
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S. Danese, C. de la Motte, B. M. R. Reyes, M. Sans, A. D. Levine, and C. Fiocchi Cutting Edge: T Cells Trigger CD40-Dependent Platelet Activation and Granular RANTES Release: A Novel Pathway for Immune Response Amplification J. Immunol., February 15, 2004; 172(4): 2011 - 2015. [Abstract] [Full Text] [PDF]
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F. Cipollone, B. Rocca, and C. Patrono Cyclooxygenase-2 Expression and Inhibition in Atherothrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 246 - 255. [Abstract] [Full Text]
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S. Russo, B. Bussolati, I. Deambrosis, F. Mariano, and G. Camussi Platelet-Activating Factor Mediates CD40-Dependent Angiogenesis and Endothelial-Smooth Muscle Cell Interaction J. Immunol., November 15, 2003; 171(10): 5489 - 5497. [Abstract] [Full Text] [PDF]
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Z. Mallat, A. Gojova, V. Sauzeau, V. Brun, J.-S. Silvestre, B. Esposito, R. Merval, H. Groux, G. Loirand, and A. Tedgui Rho-Associated Protein Kinase Contributes to Early Atherosclerotic Lesion Formation in Mice Circ. Res., October 31, 2003; 93(9): 884 - 888. [Abstract] [Full Text] [PDF]
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S. Verma, M. R. Buchanan, and T. J. Anderson Endothelial Function Testing as a Biomarker of Vascular Disease Circulation, October 28, 2003; 108(17): 2054 - 2059. [Full Text] [PDF]
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P. E. Szmitko, C.-H. Wang, R. D. Weisel, J. R. de Almeida, T. J. Anderson, and S. Verma New Markers of Inflammation and Endothelial Cell Activation: Part I Circulation, October 21, 2003; 108(16): 1917 - 1923. [Full Text] [PDF]
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M. K. C. Ng, C. M. Quinn, J. A. McCrohon, S. Nakhla, W. Jessup, D. J. Handelsman, D. S. Celermajer, and A. K. Death Androgens Up-Regulate Atherosclerosis-Related Genes in Macrophages From Males But Not Females: Molecular Insights Into Gender Differences in Atherosclerosis J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1306 - 1313. [Abstract] [Full Text] [PDF]
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C. R. Longo, M. B. Arvelo, V. I. Patel, S. Daniel, J. Mahiou, S. T. Grey, and C. Ferran A20 Protects From CD40-CD40 Ligand-Mediated Endothelial Cell Activation and Apoptosis Circulation, September 2, 2003; 108(9): 1113 - 1118. [Abstract] [Full Text] [PDF]
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N. Varo, J. A. de Lemos, P. Libby, D. A. Morrow, S. A. Murphy, R. Nuzzo, C. M. Gibson, C. P. Cannon, E. Braunwald, and U. Schonbeck Soluble CD40L: Risk Prediction After Acute Coronary Syndromes Circulation, September 2, 2003; 108(9): 1049 - 1052. [Abstract] [Full Text] [PDF]
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N. Varo, D. Vicent, P. Libby, R. Nuzzo, A. L. Calle-Pascual, M. R. Bernal, A. Fernandez-Cruz, A. Veves, P. Jarolim, J. J. Varo, et al. Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients: A Novel Target of Thiazolidinediones Circulation, June 3, 2003; 107(21): 2664 - 2669. [Abstract] [Full Text] [PDF]
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A. J. Grau and C. Lichy Editorial Comment: Stroke and the CD40-CD40 Ligand System: At the Hinge Between Inflammation and Thrombosis Stroke, June 1, 2003; 34(6): 1417 - 1418. [Full Text] [PDF]
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 M. C. Deregibus, S. Buttiglieri, S. Russo, B. Bussolati, and G. Camussi CD40-dependent Activation of Phosphatidylinositol 3-Kinase/Akt Pathway Mediates Endothelial Cell Survival and in Vitro Angiogenesis J. Biol. Chem., May 9, 2003; 278(20): 18008 - 18014. [Abstract] [Full Text] [PDF]
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 J. E. Freedman CD40 Ligand -- Assessing Risk Instead of Damage? N. Engl. J. Med., March 20, 2003; 348(12): 1163 - 1165. [Full Text] [PDF]
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 C.-L. Wang, Y.-T. Wu, C.-A. Liu, M.-W. Lin, C.-J. Lee, L.-T. Huang, and K. D. Yang Expression of CD40 Ligand on CD4+ T-Cells and Platelets Correlated to the Coronary Artery Lesion and Disease Progress in Kawasaki Disease Pediatrics, February 1, 2003; 111(2): e140 - 147. [Abstract] [Full Text] [PDF]
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U. Schonbeck, N. Gerdes, N. Varo, R. S. Reynolds, D. B. Horton, U. Bavendiek, L. Robbie, P. Ganz, S. Kinlay, and P. Libby Oxidized Low-Density Lipoprotein Augments and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Limit CD40 and CD40L Expression in Human Vascular Cells Circulation, December 3, 2002; 106(23): 2888 - 2893. [Abstract] [Full Text] [PDF]
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A. H. Wagner, M. Gebauer, B. Guldenzoph, and M. Hecker 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase-Independent Inhibition of CD40 Expression by Atorvastatin in Human Endothelial Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1784 - 1789. [Abstract] [Full Text] [PDF]
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L. Fuentes, M. Hernandez, F. J. Fernandez-Aviles, M. S. Crespo, and M. L. Nieto Cooperation Between Secretory Phospholipase A2 and TNF-Receptor Superfamily Signaling: Implications for the Inflammatory Response in Atherogenesis Circ. Res., October 18, 2002; 91(8): 681 - 688. [Abstract] [Full Text] [PDF]
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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C. Urbich, E. Dernbach, A. Aicher, A. M. Zeiher, and S. Dimmeler CD40 Ligand Inhibits Endothelial Cell Migration by Increasing Production of Endothelial Reactive Oxygen Species Circulation, August 20, 2002; 106(8): 981 - 986. [Abstract] [Full Text] [PDF]
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