Published online before print December 14, 2006, doi: 10.1161/01.ATV.0000255581.38523.7c
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© 2007 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Enhanced Expression of the Homeostatic Chemokines CCL19 and CCL21 in Clinical and Experimental Atherosclerosis
Possible Pathogenic Role in Plaque Destabilization
From the Research Institute for Internal Medicine (J.K.D., C.S., B.F., B.H., T.W., U.B., A.Y., W.J.S., S.S.F., P.A.), the Department of Cardiology (E.Ø., J.K., L.G.), the Institute for Surgical Research (E.Ø.), the Section of Clinical Immunology and Infectious Diseases (S.S.F., P.A.), the Rikshospitalet-Radiumhospitalet Medical Center, and The Biotechnology Centre of Oslo (K.T.), University of Oslo, Norway; the Department of Medicine and Centre for Molecular Medicine (O.O., A.-K.L.R., G.K.H.), Karolinska University Hospital, Stockholm, Sweden; and the Department of Medicine (J.K.D., A.B., O.Q.), University of California, San Diego, La Jolla, Calif.
Correspondence to Jan Kristian Damås, Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway. E-mail j.k.damas{at}medisin.uio.no
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Abstract |
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Objective— Based on their role in T-cell homing into nonlymphoid tissue, we examined the role of the homeostatic chemokines CCL19 and CCL21 and their common receptor CCR7 in coronary artery disease (CAD).
Methods and Results— We performed studies in patients with stable (n=40) and unstable (n=40) angina and healthy controls (n=20), in vitro studies in T-cells and macrophages, and studies in apolipoprotein-E–deficient (ApoE–/–) mice and human atherosclerotic carotid plaques. We found increased levels of CCL19 and CCL21 within the atherosclerotic lesions of the ApoE–/– mice, in human atherosclerotic carotid plaques, and in plasma of CAD patients. Whereas strong CCR7 expression was seen in T-cells from murine and human atherosclerotic plaques, circulating T-cells from angina patients showed decreased CCR7 expression. CCL19 and CCL21 promoted an inflammatory phenotype in T-cells and macrophages and increased matrix metalloproteinase (MMP) and tissue factor levels in the latter cell type. Although aggressive statin therapy increased CCR7 and decreased CCL19/CCL21 levels in peripheral blood from CAD patients, conventional therapy did not.
Conclusions— The abnormal regulation of CCL19 and CCL21 and their common receptor in atherosclerosis could contribute to disease progression by recruiting T-cells and macrophages to the atherosclerotic lesions and by promoting inflammatory responses in these cells.
We show increased plasma levels of the homeostatic chemokines in CCL19 and CCL21 in clinical and experimental atherosclerosis. By promoting inflammatory responses in T-cells and by inducing a matrix degrading, prothrombotic, and inflammatory phenotype in macrophages, we suggest that these chemokines could contribute to atherogenesis and plaque destabilization.
Key Words: atherosclerosis • coronary artery disease • immune system • cytokines • leukocytes
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Introduction |
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Evidence from clinical and experimental studies supports a pathogenic role for inflammation in atherosclerosis.1,2 This increasing appreciation of the importance of inflammation in atherogenesis has focused attention on molecules that direct the migration of leukocytes from the blood stream to the vessel wall.3 Chemokines are such molecules, being a family of cytokines characterized by their ability to cause directed migration of leukocytes into inflamed tissue. Several lines of evidence suggest that these chemotactic cytokines play an important role in atherogenesis and plaque destabilization.4–6
In contrast to the inflammatory chemokines, the so-called homeostatic chemokines (eg, CCL19 and CCL21) are constitutively expressed within secondary lymphoid organs.7 CCL19 and CCL21 and their receptor CCR7 play a pivotal role in lymphocyte trafficking by promoting infiltration of T-cells and dendritic cells into lymphoid tissue.8–10 However, recent studies suggest that these chemokines not only orchestrate lymphocyte and dendritic cell migration, but also regulate their immunogenic potential, possibly promoting inflammatory responses.11,12 CCL19 and CCL21 are also involved in the accumulation of lymphocytes into target organs of nonlymphoid origin, resulting in the de novo formation of lymphoid tissue, further supporting their inflammatory potential. Thus, CCL19/CCL21/CCR7 have been implicated in the pathogenesis of various autoimmune disorders such as rheumatoid arthritis, diabetes mellitus, and inflammatory bowel diseases.13–15
Based on their role in T-cell homing into nonlymphoid tissue, which potentially could be an atherosclerotic plaque, as well as their newly discovered involvement in inflammation, we examined the expression and possible role of CCL19 and CCL21 and their common receptor CCR7 in coronary artery disease (CAD). We used different approaches, including clinical studies in patients with stable and unstable angina, in vitro studies in T-cells and macrophages, as well as studies in apolipoprotein-E–deficient (ApoE–/–) mice and human atherosclerotic carotid plaques.
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Methods |
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A full description of the study population and the experimental procedures can be found in online supplemental materials (http://atvb.ahajournals.org).
Patients and Controls
In the present study we included CAD patient from 2 different populations: the angina study and the statin study. In the angina study we included angina patients undergoing clinically indicated coronary angiography in our coronary care unit were consecutively recruited for the study. In the statin study 30 patients with previous myocardial infarction (MI) without prior statin treatment were included and randomized to simvastatin 20 mg qd (n=15) or atorvastatin 80 mg qd (n=15) therapy for 6 months in an open study. For comparison, blood was collected from 35 healthy controls. Platelet-poor plasma and peripheral blood mononuclear cells (PBMCs) were obtained from both patients and controls. Cells were immediately cryopreserved for subsequent use in flow cytometry or stored in liquid nitrogen as pellets for RNA isolation. We also examined plasma levels of CCL19/CCL21 and mRNA levels of CCR7 in PBMCs in 9 patients with stable angina undergoing of percutaneous coronary intervention (PCI). For immunohistochemical analyses atherosclerotic plaques representing type VI lesions were obtained from 4 patients undergoing carotid endarterectomy due to transient ischemic attacks. As controls, nonatherosclerotic human renal artery samples were taken from 4 patients undergoing nephrectomy.
Animals and Cell Culture
We examined the expression of CCL19/CCL21/CCR7 in atherosclerosis-prone ApoE–/– mice and in ApoE–/– mice crossed with transgenic mice carrying a dominant-negative transforming growth factor (TGF)-ß receptor-II in T-cells (ApoE–/– x CD4dnTRII mice). The ascending aorta, including atherosclerotic lesions, was dissected under a microscope and immediately frozen. All animal experiments were in accordance with national guidelines and approved by the local ethical committee.
Human monocytes and CD3+ T-cells (separated from freshly isolated PBMCs) and the human monocytic cell line THP-1 were used for cell culture. At different time points, cell-free supernatants and cell pellets from the cultured cells were harvested and stored at –8°C until analysis.
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Results |
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The Expression of CCR7 and its Corresponding Ligands in CAD
Patients with both stable (n=40) and unstable (n=40) angina had significantly increased plasma levels of CCL19 and CCL21 compared with healthy controls (n=20), with particularly high levels in those with unstable disease (Figure 1A and 1B). In contrast, the mRNA levels of CCR7 were significantly reduced in PBMCs from both stable (n=15) and unstable angina (n=15) patients compared with the expression in healthy controls (n=20) with particularly low levels in unstable angina (Figure 1C). Flow cytometry analyzes of CCR7 expression in PBMCs from healthy controls (n=6) and stable (n=10) and unstable (n=12) angina patients showed that the decrease in CCR7 expression in angina patients primarily reflected a downregulation in the percentage of CCR7+CD4+ T-cells, with no significant difference between unstable and stable angina patients (Figure 1D). This latter finding could reflect that the gene and protein expression of this receptor are somewhat differently regulated and/or that real-time quantitative RT-PCR more precisely detects differences in CCR7 expression than flow cytometry, reflecting the percentage of positive cells. Nevertheless, both methods confirm that T-cells from CAD patients are characterized by markedly decreased CCR7 expression.
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The Effect of Percutaneous Coronary Intervention on CCL19/CCL21/CCR7 Expression
We next examined plasma levels of CCL19/CCL21 and mRNA levels of CCR7 in PBMCs in 9 patients with stable angina undergoing percutaneous coronary intervention (PCI) (66±8 years, 6 women and 3 men). Of note, this procedure induced a gradual increase in CCL19 levels (
2-fold increase after 24 hours, Figure 2A) and a marked and rapid increase in CCL21 (3-fold increase after 2 hours, Figure 2B). These changes in CCL19 and CCL21 levels were accompanied by a rapid and significant increase in CCR7 expression (4 hours), followed by a significant downregulation reaching levels lower than baseline expression after 24 hours (50% decrease, Figure 2C). Moreover, although not significantly, flow cytometry analyzes of PBMCs in 6 stable angina patients suggested that the rapid (4 hours) increase in CCR7 mRNA levels in PBMCs reflected an increase in the proportion of CCR7+CD4+ T-cells, before returning to baseline levels after 24 hours (data not shown). The discrepancy between mRNA levels (downregulated) and flow cytometry after 24 hours could potentially reflect that downregulation at the protein levels is delayed as compared with the gene expression of this receptor. Nevertheless, PCI, representing a mechanically induced plaque rupture, induced a similar pattern for CCL19/CCL21 expression, and in some degree also for CCR7, as the pattern that was seen in unstable angina.
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Localization of CCL19/CCL21/CCR7 in Plaques From ApoE–/– Mice
To further characterize CCR7 and its corresponding ligands in atherosclerosis, we examined the expression of the CCL19/CCL21/CCR7 proteins by immunohistochemistry within the atherosclerotic plaques of aorta in a murine model of atherosclerosis, the ApoE–/– mouse (supplemental Figure I, available online at http://atvb.ahajournals.org). Although weak CCL19, CCL21, and CCR7 immunoreactivities were observed in smooth muscle cells (SMCs) of the nonatherosclerotic vessel wall, stronger immunostaining for both the ligands, and the receptor was found within the atherosclerotic lesions, both in regions with predominantly CD68+ macrophages and in areas rich in CD3+ T-cells with particularly strong CCR7 staining in T-cell areas. Crossing of ApoE–/– mice with transgenic mice carrying a dominant negative transforming growth factor (TGF)-ß receptor II in T-cells (ApoE–/– x CD4dnTßRII mice) results in a strain with markedly enhanced atherosclerosis, displaying increased T-cell activation, activated macrophages, and reduced collagen.16 In these mice, the area with CCL19, CCL21, and CCR7 immunostaining was increased in proportion with the increase in lesion size, suggesting a "dose–response"–like pattern for these mediators along with enhanced atherosclerosis in mice lacking TGF-ß mediated inhibition of T-cell activation (supplemental Figure I). In contrast, in areas with debris and in foam cell–like cells, only weak CCL19, CCL21, and CCR7 immunostaining was observed in both mouse models, with particularly weak CCR7 staining in the ApoE–/– x CD4dnTßRII mice (supplemental Figure I).
Expression of CCL19/CCL21/CCR7 in Human Atherosclerotic Lesions
To determine the cellular localization of CCL19/CCL21/CCR7 in human atherosclerotic disease, immunohistochemical analysis was performed on carotid plaques obtained from 4 patients undergoing carotid endarterectomy attributable to transient ischemic attacks (Figure 3). Immunostaining of serial sections with antibodies against CCL19, CCL21, and CCR7 as well as the cellular markers CD3 (T-cells), calprotectin (monocytes/macrophages), vimentin (fibroblasts), and SMC actin (SMCs) showed CCL19 and CCL21 immunoreactivities both in macrophages and in T-cells. CCR7 immunostaining was predominantly seen in T-cells within the atherosclerotic lesions with weaker immunostaining in areas with macrophages/foam cells. In nonatherosclerotic renal arteries, CCL19, CCL21, and CCR7 immunostaining was only found in SMCs (data not shown).
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The Regulation of CCR7 Expression in THP-1 Macrophages
Atherosclerotic lesions were characterized by low CCR7 expression in foam cell–like cells. To further elucidate this issue, we examined CCR7 mRNA levels during macrophage differentiation. Although the expression of CCR7 in freshly isolated monocytes and undifferentiated THP-1 cells was very low, the differentiation of THP-1 cells to macrophages with PMA (72 hours) resulted in a marked upregulation of CCR7 mRNA levels (supplemental Figure IIA). However, when these macrophages were further stimulated with oxLDL (20 µg/mL for 24 hours in medium containing 10% FCS), resulting in foam cell formation, the CCR7 expression was markedly attenuated (supplemental Figure IIA). Thus, although macrophage differentiation enhances CCR7 expression, foam cell formation markedly inhibits this upregulation, a finding that is consistent with the weak CCR7 immunostaining in areas with foam cell–like cells in plaques from ApoE–/– and ApoE–/– x CD4dnTßRII mice.
cAMP Increases CCR7 Expression During Macrophage Differentiation
The sympathetic nervous system shows increased activity in angina patients.17 Through ß-adrenergic receptor signaling, this could increase cAMP formation. Prostaglandin (PG) E2, another mediator that increases intracellular cAMP levels, has been reported to enhance CCR7 expression in dendritic cells,18 and we therefore examined the ability of cAMP to modulate CCR7 expression in T-cells and monocytes/macrophages. As shown in supplemental Figure IIB, the cAMP agonist Sp-8-Br-cAMPS and forskolin, a direct activator of adenylyl cyclase, known to increase the endogenous cAMP levels, markedly increased CCR7 expression during THP-1 cell differentiation to macrophages. Conversely, Rp-8-Br-cAMPS, a complementary antagonist to Sp-8-Br-cAMPS, downregulated CCR7 expression in these cells. Moreover, the ß-adrenergic receptor agonist isoproterenol, known to increase endogenous cAMP levels, increased CCR7 expression in freshly isolated human monocytes after culturing for 24 hours (supplemental Figure IIC). In contrast to the cAMP elevating agents, inflammatory stimuli such as TLR2 and TLR4 agonists and tumor necrosis factor (TNF)
downregulated CCR7 expression during THP-1 cell differentiation, although the effect of lipopolysaccharide (LPS) was rather modest and nonsignificant (supplemental Figure IID). Unlike the effects on macrophages, the cAMP agonist and forskolin had no effect on CCR7 expression in T-cells (data not shown).
Effects of CCL19 and CCL21 in T-Cells
Our findings suggest that T-cells in atherosclerosis, and particularly in advanced disease, are characterized by increased CCR7 expression in the plaque. To map any possible pathogenic consequences of these alterations, we examined the effects of CCL19 and CCL21 on the release of cytokines in T-cells from 8 healthy controls, 8 patients with stable angina, and 8 patients with unstable angina. CCL21 markedly increased the release of interleukin (IL)-8, TNF, and IFN
in T-cells from healthy controls and stable angina patients, with a more modest effect of CCL19 (Figure 4). However, whereas the spontaneous release of these cytokines was significantly increased in T-cells from unstable angina patients, the CCL19 and CCL21-mediated responses were very modest, potentially reflecting that the reduced CCR7 mRNA expression in PBMCs from these patients affects their functional responses (Figure 4). In contrast to these effects on inflammatory cytokines, no effects were seen on IL-10 in either angina patients or controls (data not shown). Neutralizing antibodies against CCR7, but not isotype-matched control antibodies, totally abolished the inflammatory response of CCL19 and CCL21 in T-cells from both angina patients and healthy controls (data not shown).
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Effects of CCL19 and CCL21 in THP-1 Macrophages
Although to a lesser degree than in T-cells, also macrophages within the atherosclerotic lesions were found to express CCR7, colocalized with high expression of its ligands. When examining the effects of the CCR7 ligands on THP-1 macrophages, we found that CCL19 and particularly CCL21 significantly increased the release of the inflammatory cytokines IL-8 and TNF in these cells (supplemental Figure III). Moreover, and with relevance to plaque destabilization and thrombus formation, both CCL19 and CCL21 increased MMP activity and TF levels in THP-1 macrophages, with markedly enhancing effect of CCL21 on TF as the most prominent finding (supplemental Figure III). Neutralizing antibodies against CCR7, but not isotype-matched control antibodies, totally abolished the CCL19- and CCL21-mediated responses in THP-1 cells, demonstrating that these effects are mediated through CCR7 activation (data not shown).
Effects of Statins on CCR7 Expression
Experimental and clinical data indicate that statins may confer cardiovascular benefits in addition to the lipid lowering activity at least partly by modulating the inflammatory arm of atherosclerosis.19,20 We therefore examined the ability of statins to modulate CCR7 expression in CAD by analyzing the effect of simvastatin (20 mg qd) and atorvastatin (80 mg qd) on CCR7 expression in PBMCs in 30 CAD patients receiving statin therapy for 6 months (see supplemental Methods). As expected, treatment with statins reduced plasma levels of total cholesterol, LDL-cholesterol, and triglycerides (supplemental Table II). However, although no changes was seen in CCR7 expression in PBMCs during low-dose simvastatin therapy (n=15, representing conventional statin therapy), PBMCs from those patients who had received high-dose atorvastatin (n=15, representing aggressive statin therapy) had significantly higher mRNA levels of this receptor after 6 months of therapy (Figure 5). Moreover, flow cytometry analyses suggested that these changes reflected an increase in CCR7+CD4+T-cells (Figure 5 and supplemental Figure IV). Finally, during high-dose atorvastatin therapy, but not during low-dose simvastatin therapy, the increase in CCR7 expression was accompanied by a significant decrease in plasma levels of its corresponding ligands, CCL19 and CCL21 (Figure 5).
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Discussion |
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In the present study, we show disturbed regulation of the homeostatic chemokines CCL19/CCL21 and their common receptor CCR7 in both clinical and experimental atherosclerosis. We found increased levels of CCL19 and CCL21 within the atherosclerotic lesions of ApoE–/– mice and in human atherosclerotic carotid plaques as well as in plasma of CAD patients with particularly high expression in unstable and advanced disease. However, although strong CCR7 expression was seen in T-cells in murine and human atherosclerotic plaques, circulating T-cells from angina patients showed decreased CCR7 expression, possibly reflecting redistribution of CCR7+ T cells toward the atherosclerotic lesion.
The CC chemokine receptor CCR7 has been identified as a key regulator of homeostatic T-cell trafficking to secondary lymphoid organs.7–10 However, recent studies suggest that this receptor also can be involved in the abnormal recruitment of T-cells from the circulation to sites of inflammation.13–15 In the present study we show enhanced CCR7 expression in T-cells from both murine and human atherosclerotic lesions. In contrast to this, we found that mononuclear cells from angina patients showed decreased mRNA expression of CCR7 in peripheral blood, primarily reflecting a decreased proportion of CCR7+CD4+T-cells. In contrast to CCR7, its ligands, ie, CCL19 and CCL21, showed enhanced expression both within the atherosclerotic lesions, with strong immunostaining in both T-cells and macrophages, and in peripheral blood, illustrating that CCR7 and its ligands are differently regulated. Although several additional experiments will have to be performed, based on recent studies,21–23 it is tempting to hypothesize that the different expression pattern of CCR7+T-cells between peripheral blood and the atherosclerotic lesions reflect a distribution of these cells toward the inflammatory atherosclerotic lesions during plaque progression. Within the lesions, these T-cells, as well as CCR7 expressing macrophages, are exposed to increased levels of CCL19 and CCL21, potentially promoting inflammation, MMP activation, and thrombus formation. There is a number of autoimmune diseases whose pathology relies on aberrant T-cell infiltration, such as rheumatoid arthritis and inflammatory bowel disease, and aberrant CCL19/CCL21/CCR7 expression has shown to be involved in these processes.13,15,24 The findings in the present study suggest that these molecules also could be involved in the promotion of aberrant lymphocyte infiltration and activation into atherosclerotic lesions.
Macrophages expressing CCR7 have recently been reported in inflammatory skin disorders.25 Herein we found increased expression of CCL19/CCL21, and in some degree also of CCR7, in macrophages within the inflamed atherosclerotic vessel wall. Furthermore, we show that CCL19 and particularly CCL21 induce inflammatory responses not only in T-cells, but also in THP-1 macrophages by promoting release of IL-8 and TNF, and as for T-cells also of IFN. Marsland et al have previously shown that CCL19 and CCL21 are potent inducers of inflammatory cytokines in dendritic cells with a secondary promotion of a Th1-like phenotype in adjacent T-cells.11 In the present study, we show that CCL19/CCL21 directly induce an inflammatory response in T-cells. Moreover, in addition to inflammation, these chemokines seem to enhance the matrix degrading and the prothrombotic potential of macrophages by increasing MMP and TF levels. If such mechanisms also are operating within the atherosclerotic lesion, they may in addition to promoting an inflammatory Th1 phenotype, also induce a matrix degrading, inflammatory, and prothrombotic phenotype in CCR7 expressing macrophages. Based on the high levels of CCL19/CCL21 in angina patients, with particularly high levels in unstable disease, as well as the increased expression of these molecules in symptomatic human carotid plaques, these mediators could potentially contribute to atherogenesis and plaque destabilization with subsequent thrombus formation and development of acute ischemic events.
Alghouth there was no CCR7 expression in freshly isolated monocytes, THP-1 macrophages showed increased CCR7 expression. In the present study we show that cAMP further enhances this upregulation of CCR7 expression during macrophage differentiation. ß-adrenergic receptor activation is an important stimulus for elevation of intracellular cAMP levels, and as CAD patients are known to have persistently increased catecholamine levels,17 our finding could be of relevance also in relation to CAD. Indeed, we showed a CCR7-inducing effect in monocytes of the ß-adrenergic receptor agonist isoproterenol, further supporting such a notion. In contrast to the cAMP elevating agents, inflammatory stimuli like TLR2 and TLR4 ligands and TNF as well as oxLDL downregulated CCR7 expression during macrophage differentiation. These data illustrate the complex regulation of CCR7 expression in macrophages within an inflammatory and lipid-rich lesion such as an atherosclerotic plaque, being exposed to both downregulatory and enhancing stimuli.
Recent studies suggest that the beneficial effects of statins in atherosclerotic disorders may be related to their immunomodulatory properties.19,20 Herein we show that these drugs are able to increase the proportion of CCR7+CD4+ T-cells in CAD patients, accompanied by a decrease in plasma levels of its ligands. Whether this observation reflects redistribution from the inflamed atherosclerotic lesions to the circulation is at present not clear. However, 2 very recent articles have suggested that CCR7 may play an important role in emigration of T-cells from inflamed tissue with particularly pronounced effect on mobilization of the CCR7+CD4+ T-cells.26,27 Moreover, Yilmaz et al have recently showed that statin preincubated dendritic cells exhibited an immature phenotype with a significantly lower expression of CCR7,28 suggesting that these medications also could modulate CCR7 expression in macrophages within the plaque. Although aggressive statin therapy induced changes in CCR7/CCL19/CCL21 expression, conventional therapy did not. Whether this difference in their immunomodulatory potential reflects drug- or dose-dependent differences or both should be further investigated. Nevertheless, some recent studies suggest that an intensive lipid-lowering statin regimen provides greater protection against cardiovascular events than does a standard regimen,29 and it is possible that the superiority of high-dose atorvastain also involves more potent immunomodulatory effects of this medication.
In the present study, we show abnormal regulation of the homeostatic chemokines CCL19 and CCL21 and their common receptor CCR7 in atherosclerosis with particularly disturbed expression in unstable and advanced disease. By recruiting T-cells and macrophages to the atherosclerotic lesions, by promoting inflammatory responses in T-cells, and by inducing a matrix degrading, prothrombotic, and inflammatory phenotype in macrophages, these chemokines could contribute to atherogenesis and plaque destabilization, possibly representing novel targets for therapy in CAD.30,31
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Acknowledgments |
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Sources of Funding
This work was supported by grants from the Research Council of Norway, National Institutes of Health grant HL56989 (La Jolla Specialized Center of Research in Molecular Medicine and Atherosclerosis), Norwegian Council of Cardiovascular Research, Swedish Heart-Lung Foundation, Medinnova Foundation, "Aktieselskapet Freia Chocoladefabriks" Medical Foundation, and Blix Family Legacy.
Disclosures
None.
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Footnotes |
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Original received March 10, 2006; final version accepted November 29, 2006.
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