Erwin Wijnands

Maastricht University, Maestricht, Limburg, Netherlands

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Publications (29)186.09 Total impact

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    ABSTRACT: During obesity, inflammatory ‘M1’ macrophages infiltrate adipose tissue (AT). These ‘M1’ AT macrophages (ATMs) express the dendritic cell marker CD11c. Dendritic cells are immune regulators that promote insulin resistance. However, it is unclear whether and how CD11c+ ATMs differ from dendritic cells and if they are activated by obesity.
    No preview · Article · Nov 2015
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    ABSTRACT: Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization. Ldlr(-/-) mice were transplanted with batf3(-/-) or wt bone marrow and put on a western type diet. Hematopoietic batf3 deficiency sharply decreased CD8α(+) DC numbers in spleen and lymph nodes (>80%; P < 0,001). Concordantly, batf3(-/-) chimeras had a 75% reduction in OT-I cross-priming capacity in vivo. Batf3(-/-) chimeric mice did not show lower Tcell or other leukocyte subset numbers. Despite dampened cross-presentation capacity, batf3(-/-) chimeras had equal atherosclerosis burden in aortic arch and root. Likewise, batf3(-/-) chimeras and wt mice revealed no differences in parameters of plaque stability: plaque Tcell infiltration, cell death, collagen composition, and macrophage and vascular smooth muscle cell content were unchanged. These results show that CD8α(+) DC loss in hyperlipidemic mice profoundly reduces cross-priming ability, nevertheless it does not influence lesion development. Taken together, we clearly demonstrate that CD8α(+) DC-mediated cross-presentation does not significantly contribute to atherosclerotic plaque formation and stability.
    Full-text · Article · Oct 2015 · Scientific Reports
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    ABSTRACT: A disintegrin and metalloproteinase domain 10 (ADAM10) is a metalloprotease involved in cleavage of various cell surface molecules, such as adhesion molecules, chemokines, and growth factor receptors. Although we have previously shown an association of ADAM10 expression with atherosclerotic plaque progression, a causal role of ADAM10 in atherosclerosis has not been investigated. Bone marrow from conditional knockout mice lacking Adam10 in the myeloid lineage or from littermate controls was transplanted into lethally irradiated Ldlr(-/-) mice on an atherogenic diet. Myeloid Adam10 deficiency did not affect plaque size, but it increased plaque collagen content. Matrix metalloproteinase 9 and 13 expression and matrix metalloproteinase 2 gelatinase activity were significantly impaired in Adam10-deficient macrophages, whereas their capacity to stimulate collagen production was unchanged. Furthermore, relative macrophage content in advanced atherosclerotic lesions was decreased. In vitro, Adam10-deficient macrophages showed reduced migration toward monocyte chemoattractant protein-1 and transmigration through collagen. In addition, Adam10-deficient macrophages displayed increased anti-inflammatory phenotype with elevated IL-10, and reduced production of proinflammatory tumor necrosis factor, IL-12, and nitric oxide in response to lipopolysaccharide. These data suggest a critical role of Adam10 for leukocyte recruitment, inflammatory mediator production, and extracellular matrix degradation. Thereby, myeloid ADAM10 may play a causal role in modulating atherosclerotic plaque stability. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · American Journal Of Pathology
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    ABSTRACT: Aims: Advanced glycation end-products (AGEs) and their precursors have been associated with the development of atherosclerosis. We recently discovered that glyoxalase 1 (GLO1), the major detoxifying enzyme for AGE precursors, is decreased in ruptured human plaques, and that levels of AGEs are higher in rupture-prone plaques. We here investigated whether overexpression of human GLO1 in ApoE(-/-) mice could reduce the development of atherosclerosis. Methods and results: We crossed C57BL/6 ApoE(-/-) mice with C57BL/6 GLO1 overexpressing mice (huGLO1(+/-)) to generate ApoE(-/-) (n = 16) and ApoE(-/-) huGLO1(+/-) (n = 20) mice. To induce diabetes, we injected a subset with streptozotocin (STZ) to generate diabetic ApoE(-/-) (n = 8) and ApoE(-/-) huGLO1(+/-) (n = 13) mice. All mice were fed chow and sacrificed at 25 weeks of age. The GLO1 activity was three-fold increased in huGLO1(+/-) aorta, but aortic root lesion size and phenotype did not differ between mice with and without huGLO1(+/-) overexpression. We detected no differences in gene expression in aortic arches, in AGE levels and cytokines, in circulating cells, and endothelial function between ApoE(-/-) mice with and without huGLO1(+/-) overexpression. Although diabetic mice showed decreased GLO1 expression (P < 0.05) and increased lesion size (P < 0.05) in comparison with non-diabetic mice, GLO1 overexpression also did not affect the aortic root lesion size or inflammation in diabetic mice. Conclusion: In ApoE(-/-) mice with or without diabetes, GLO1 overexpression did not lead to decreased atherosclerotic lesion size or systemic inflammation. Increasing GLO1 levels does not seem to be an effective strategy to reduce glycation in atherosclerotic lesions, likely due to increased AGE formation through GLO1-independent mechanisms.
    No preview · Article · Aug 2014 · Cardiovascular Research
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    ABSTRACT: Atherosclerosis is a lipid-driven inflammatory disease of the vessel wall, characterized by the chronic activation of macrophages. We investigated whether the helminth-derived antigens [soluble egg antigens (SEAs)] could modulate macrophage inflammatory responses and protect against atherosclerosis in mice. In bone marrow-derived macrophages, SEAs induce anti-inflammatory macrophages, typified by high levels of IL-10 and reduced secretion of proinflammatory mediators. In hyperlipidemic LDLR(-/-) mice, SEA treatment reduced plaque size by 44%, and plaques were less advanced compared with PBS-injected littermate controls. The atheroprotective effect of SEAs was found to be mainly independent of cholesterol lowering and T-lymphocyte responses but instead could be attributed to diminished myeloid cell activation. SEAs reduced circulating neutrophils and inflammatory Ly6C(high) monocytes, and macrophages showed high IL-10 production. In line with the observed systemic effects, atherosclerotic lesions of SEA-treated mice showed reduced intraplaque inflammation as inflammatory markers [TNF-α, monocyte chemotactic protein 1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and CD68], neutrophil content, and newly recruited macrophages were decreased. We show that SEA treatment protects against atherosclerosis development by dampening inflammatory responses. In the future, helminth-derived components may provide novel opportunities to treat chronic inflammatory diseases, as they diminish systemic inflammation and reduce the activation of immune cells.-Wolfs, I. M. J., Stöger, J. L., Goossens, P., Pöttgens, C., Gijbels, M. J. J., Wijnands, E., van der Vorst, E. P. C., van Gorp, P., Beckers, L., Engel, D., Biessen, E. A. L., Kraal, G., van Die, I., Donners, M. M. P. C., de Winther, M. P. J. Reprogramming macrophages to an anti-inflammatory phenotype by helminth antigens reduces murine atherosclerosis.
    Full-text · Article · Sep 2013 · The FASEB Journal
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    ABSTRACT: Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this process. We recently reported that microRNA-155 is a key mediator of cardiac inflammation and injury in infectious myocarditis. Here we investigated the impact of miRNA-155 manipulation in hypertensive heart disease. Genetic loss or pharmacological inhibition of the leukocyte-expressed microRNA-155 in mice markedly reduced cardiac inflammation, hypertrophy and dysfunction upon pressure overload. These alterations were macrophage-dependent, as in vivo cardiomyocyte-specific microRNA-155 manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild type into microRNA-155 knockout animals rescued the cardiomyocytes' hypertrophic response and vice versa. In vitro, media from microRNA-155 knockout macrophages blocked the hypertrophic growth of stimulated cardiomyocytes, confirming that macrophages influence myocyte growth in a miR-155-dependent paracrine manner. These effects were at least partly mediated by the direct microRNA-155 target Suppressor of Cytokine Signaling 1 (Socs1), as Socs1 knockdown in microRNA-155 knockout macrophages largely restored their hypertrophy-stimulating potency. Our findings reveal that microRNA-155 expression in macrophages promotes cardiac inflammation, hypertrophy and failure in response to pressure overload. These data support the causative significance of inflammatory signaling in hypertrophic heart disease and demonstrate the feasibility of therapeutic microRNA targeting of inflammation in heart failure.
    Full-text · Article · Aug 2013 · Circulation
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    ABSTRACT: Purpose: Viral myocarditis is a life-threatening disease characterized by severe cardiac inflammation that can result in sudden death or congestive heart failure in previously healthy adults, and there are no current therapies. Inflammatory cell recruitment is necessary to eliminate the virus but also plays a large role in the pathophysiology therefore understanding the cellular and molecular steps of cardiac inflammation is essential in order to develop new therapies. Methods: In the coxsackie B3 (CVB3) murine model of viral myocarditis, transcript levels of stabilin-1, a transmembranal glycoprotein, increased 3-fold in heart tissue at 9 days post infection. Immunohistochemical detection of stabilin-1 showed an increase of stabilin-1 expression in mouse heart tissue after CVB3 infection and in endomyocardial biopsies from patients with viral myocarditis. Furthermore, stabilin-1 was expressed on mac-3 positive cells in the mouse model and CD68-positve cells in the human biopsies. Stabilin-1 null (KO) mice showed increased cardiac related mortality when challenged with the CVB3 virus in comparison to wild type (WT) mice. Histological analysis of the heart showed that the stabilin-1 KO mice had increased cardiomyocyte necrosis and CD3+ lymphocyte infiltration but lower levels of macrophages cells, in comparison to WT animals. In vitro, Stabilin-1 KO monocytes (cd11b+ cells) had a significant decreased adherence to endothelial cells as compared to WT cells. Fibronectin was identified as the binding partner of stabilin-1, through a 2-yeast hybrid screen and GST-pulldown. Furthermore, Stabilin-1 KO monocytes (cd11b+ cells) had a significant decreased adherence to fibronectin -coated plastic as compared to WT cells. Conclusions: This study shows that the transmembranal glycoprotein Stabilin-1 is up regulated during myocarditis, both in the animal model and in patients with acute fulminant myocarditis. Stabilin-1 is needed for the recruitment of monocytes to the site of infection and interacts with fibronectin in order for monocytes to adhere. These data demonstrate that Stabilin-1 and monocyte recruitment are necessary in order to eliminate the virus and prevent exaggerated inflammation during viral myocarditis.
    Preview · Article · Aug 2013 · European Heart Journal

  • No preview · Article · Apr 2013 · European Journal of Clinical Investigation

  • No preview · Article · Apr 2013 · European Journal of Clinical Investigation
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    ABSTRACT: Leukocyte chemotaxis is deemed instrumental in initiation and progression of atherosclerosis. It is mediated by G-protein-coupled receptors (e.g., CCR2 and CCR5), the activity of which is controlled by G-protein-coupled receptor kinases (GRKs). In this study, we analyzed the effect of hematopoietic deficiency of a potent regulator kinase of chemotaxis (GRK2) on atherogenesis. LDL receptor-deficient (LDLr(-)(/)(-)) mice with heterozygous hematopoietic GRK2 deficiency, generated by bone marrow transplantation (n=15), displayed a dramatic attenuation of plaque development, with 79% reduction in necrotic core and increased macrophage content. Circulating monocytes decreased and granulocytes increased in GRK2(+/)(-) chimeras, which could be attributed to diminished granulocyte colony-forming units in bone marrow. Collectively, these data pointed to myeloid cells as major mediators of the impaired atherogenic response in GRK2(+/)(-) chimeras. LDLr(-)(/)(-) mice with macrophage/granulocyte-specific GRK2 deficiency (LysM-Cre GRK2(flox/flox); n=8) failed to mimic the aforementioned phenotype, acquitting these cells as major responsible subsets for GRK2 deficiency-associated atheroprotection. To conclude, even partial hematopoietic GRK2 deficiency prevents atherosclerotic lesion progression beyond the fatty streak stage, identifying hematopoietic GRK2 as a potential target for intervention in atherosclerosis.-Otten, J. J. T., de Jager, S. C. A., Kavelaars, A., Seijkens, T., Bot, I., Wijnands, E., Beckers, L., Westra, M. M., Bot, M., Busch, M., Bermudez, B., van Berkel, T. J. C., Heijnen, C. J., Biessen, E. A. L. Hematopoietic G-protein-coupled receptor kinase 2 deficiency decreases atherosclerotic lesion formation in LDL receptor-knockout mice.
    Full-text · Article · Oct 2012 · The FASEB Journal
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    ABSTRACT: Viral myocarditis results from an adverse immune response to cardiotropic viruses, which causes irreversible myocyte destruction and heart failure in previously healthy people. The involvement of microRNAs and their usefulness as therapeutic targets in this process are unknown. To identify microRNAs involved in viral myocarditis pathogenesis and susceptibility. Cardiac microRNAs were profiled in both human myocarditis and in Coxsackievirus B3-injected mice, comparing myocarditis-susceptible with nonsusceptible mouse strains longitudinally. MicroRNA responses diverged depending on the susceptibility to myocarditis after viral infection in mice. MicroRNA-155, -146b, and -21 were consistently and strongly upregulated during acute myocarditis in both humans and susceptible mice. We found that microRNA-155 expression during myocarditis was localized primarily in infiltrating macrophages and T lymphocytes. Inhibition of microRNA-155 by a systemically delivered LNA-anti-miR attenuated cardiac infiltration by monocyte-macrophages, decreased T lymphocyte activation, and reduced myocardial damage during acute myocarditis in mice. These changes were accompanied by the derepression of the direct microRNA-155 target PU.1 in cardiac inflammatory cells. Beyond the acute phase, microRNA-155 inhibition reduced mortality and improved cardiac function during 7 weeks of follow-up. Our data show that cardiac microRNA dysregulation is a characteristic of both human and mouse viral myocarditis. The inflammatory microRNA-155 is upregulated during acute myocarditis, contributes to the adverse inflammatory response to viral infection of the heart, and is a potential therapeutic target for viral myocarditis.
    No preview · Article · Jun 2012 · Circulation Research
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    ABSTRACT: AimsThe importance of transforming growth factor beta (TGFβ) as an immune regulatory cytokine in atherosclerosis has been established. However, the role of TGFβ signalling in dendritic cells (DCs) and in DC-mediated T cell proliferation and differentiation in atherosclerosis is unknown.Methods and resultsHere, we investigated the effect of disrupted TGFβ signalling in DCs on atherosclerosis by using mice carrying a transgene resulting in functional inactivation of TGFβ receptor II (TGFβRII) signalling in CD11c(+) cells (Apoe(-/-)CD11cDNR). Apoe(-/-)CD11cDNR mice exhibited an over two-fold increase in the plaque area compared with Apoe(-/-) mice. Plaques of Apoe(-/-)CD11cDNR mice showed an increase in CD45(+) leucocyte content, and specifically in CD3(+), CD4(+) and CD8(+) cells, whereas macrophage content was not affected. In lymphoid organs, Apoe(-/-)CD11cDNR mice had equal amounts of CD11c(+) cells, and CD11c(+)CD8(+) and CD11c(+)CD8(-) subsets, but showed a subtle shift in the CD11c(+)CD8(-) population towards the more inflammatory CD11c(+)CD8(-)CD4(-) DC subset. In addition, the number of plasmacytoid-DCs decreased. Maturation markers such as MHCII, CD86 and CD40 on CD11c(hi) cells did not change, but the CD11cDNR DCs produced more TNFα and IL-12. CD11c(+) cells from CD11cDNR mice strongly induced T-cell proliferation and activation, resulting in increased amounts of effector T cells producing high amounts of Th1 (IFN-γ), Th2 (IL-4, IL-10), Th17 (IL-17), and Treg (IL-10) cytokines.Conclusion Here, we show that loss of TGFβRII signalling in CD11c(+) cells induces subtle changes in DC subsets, which provoke uncontrolled T cell activation and maturation. This results in increased atherosclerosis and an inflammatory plaque phenotype during hypercholesterolaemia.
    No preview · Article · May 2012 · European Heart Journal
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    ABSTRACT: Rationnel L’obésité constitue un facteur de risque pour les pathologies métaboliques et vasculaires telles que l’insulino-résistance, la stéatose hépatique ou l’athérosclérose. L’inflammation joue un rôle pivot dans le développement des désordres métaboliques. Il est clairement établi que les cellules immunitaires s’accumulent dans le tissu adipeux mais leurs interactions, entres elles ou avec les adipocytes, sont encore mal connues. Nous avons montré que la déficience en CD40 ligand améliore la prise de poids, l’inflammation adipeuse et la sensibilité à l’insuline chez la souris obèse. Notre objectif est ici d’étudier le rôle du récepteur CD40 et des molécules adaptatrices TRAF. Matériels et méthodes Des souris déficientes en CD40 re-exprimant ou non un CD40 présentant des mutations modifiant les sites de liaison aux TRAF (CD40-WT, CD40-TRAF2, CD40-TRAF6, CD40-TRAF2/6) ont reçu une alimentation hyperlipidique (18–20 semaines). Les paramètres inflammatoires et métaboliques ont été évalués. Résultats Contrairement au déficit en CD40L, celui en CD40 ne protège pas de la prise de poids, augmente l’infiltration des CD3+ dans le tissu adipeux et l’intolérance au glucose. Les souris déficientes pour la signalisation TRAF2/6 présentent un gain de poids accéléré comparées aux autres génotypes. À poids égal, ces souris sont plus fortement intolérantes au glucose et insulino-résistantes. L’infiltration de leur tissu adipeux par les lymphocytes T pro-inflammatoires est augmentée alors que celle des lymphocytes T régulateurs est réduite. La stéatose hépatique est nettement augmentée chez les souris CD40-TRAF2/6. Le phénotype des TRAF2 est similaire, bien que moins prononcé, tandis que celui des TRAF6 est peu ou pas modifié. Conclusion De façon inattendue, le déficit en CD40 aggrave les complications métaboliques et inflammatoires de l’obésité. L’absence de signalisation CD40-TRAF2/6 amplifie les effets délétères du régime gras, suggérant un rôle protecteur de cette voie inflammatoire. Sa modulation pourrait constituer une cible d’intérêt dans le traitement de l’obésité et complications associées.
    No preview · Article · Mar 2012 · Diabetes & Metabolism
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    ABSTRACT: Obese adipose tissue shows hallmarks of chronic inflammation, which promotes the development of metabolic disorders. The mechanisms by which immune cells interact with each other or with metabolism-associated cell types, and the players involved, are still unclear. The CD40-CD40L costimulatory dyad plays a pivotal role in immune responses and in diseases such as atherosclerosis and may therefore be a mediator of obesity. Here we investigated whether CD40L is involved in adipose tissue inflammation and its associated metabolic changes. To assess a putative role of CD40L in obesity in vivo, we evaluated metabolic and inflammatory consequences of 18 weeks of high-fat feeding in CD40L(+/+) and CD40L(-/-) mice. In addition, C57Bl6 mice were injected with neutralizing anti-CD40L (αCD40L) antibody for 12 weeks while being fed a high-fat diet. Genetic deficiency of CD40L attenuated the development of diet-induced obesity, hepatic steatosis, and increased systemic insulin sensitivity. In adipose tissue, it impaired obesity-induced immune cell infiltration and the associated deterioration of glucose and lipid metabolism. Accordingly, αCD40L treatment improved systemic insulin sensitivity, glucose tolerance, and CD4(+) T-cell infiltration in adipose tissue with limited effects on adipose tissue weight. CD40L plays a crucial role in the development of obesity-induced inflammation and metabolic complications.
    Preview · Article · Aug 2011 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: Caveolin-1 plays a crucial role in atherosclerosis, which is mainly attributed to its effects on low-density-lipoprotein (LDL) transcytosis. However, caveolin-1 has also been implicated in the regulation of inflammation. We investigated the effects of caveolin-1 deficiency in atherosclerosis with its accompanying changes in plaque- and lymphoid-related immunology and inflammation. Cav1(-/-)Apoe(-/-) mice exhibited a 15-fold reduction in plaque size with plaques containing fewer macrophages, T cells, and neutrophils. Intravital microscopy revealed 83% less leukocyte adhesion to the vessel wall in Cav1(-/-)Apoe(-/-) mice, which could be attributed to reduced endothelial chemokine ligand-2 (CCL-2/MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Caveolin-1 deficiency resulted in a 57% increase in regulatory T cells and a 4% decrease in CD4(+) effector T cells in lymphoid organs. Bone marrow transplantations revealed that Cav1(-/-)Apoe(-/-) mice receiving Cav1(+/+)Apoe(-/-) or Cav1(-/-)Apoe(-/-) bone marrow presented 4- to 4.5-fold smaller plaques with no additional phenotypic changes. In contrast, atherosclerosis was not affected in Cav1(+/+) Apoe(-/-) recipients receiving Cav1(-/-)Apoe(-/-) or Cav1(+/+) Apoe(-/-) bone marrow. However, the presence of Cav1(-/-) Apoe(-/-) bone marrow was associated with an anti-inflammatory T-cell profile. Our study reveals that nonhematopoietic caveolin-1 determines plaque size, whereas hematopoietic caveolin-1 regulates lymphoid immune-modulation. However, both are required for phenotypic modulation of plaques.
    Full-text · Article · Jul 2011 · The FASEB Journal
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    ABSTRACT: CD40 ligand (CD40L), identified as a costimulatory molecule expressed on T cells, is also expressed and functional on platelets. We investigated the thrombotic and inflammatory contributions of platelet CD40L in atherosclerosis. Although CD40L-deficient (Cd40l(-/-)) platelets exhibited impaired platelet aggregation and thrombus stability, the effects of platelet CD40L on inflammatory processes in atherosclerosis were more remarkable. Repeated injections of activated Cd40l(-/-) platelets into Apoe(-/-) mice strongly decreased both platelet and leukocyte adhesion to the endothelium and decreased plasma CCL2 levels compared with wild-type platelets. Moreover, Cd40l(-/-) platelets failed to form proinflammatory platelet-leukocyte aggregates. Expression of CD40L on platelets was required for platelet-induced atherosclerosis as injection of Cd40l(-/-) platelets in contrast to Cd40l(+/+) platelets did not promote lesion formation. Remarkably, injection of Cd40l(+/+), but not Cd40l(-/-), platelets transiently decreased the amount of regulatory T cells (Tregs) in blood and spleen. Depletion of Tregs in mice injected with activated Cd40l(-/-) platelets abrogated the athero-protective effect, indicating that CD40L on platelets mediates the reduction of Tregs leading to accelerated atherosclerosis. We conclude that platelet CD40L plays a pivotal role in atherosclerosis, not only by affecting platelet-platelet interactions but especially by activating leukocytes, thereby increasing platelet-leukocyte and leukocyte-endothelium interactions.
    Full-text · Article · Nov 2010 · Blood

  • No preview · Conference Paper · Nov 2010

  • No preview · Conference Paper · Nov 2010

  • No preview · Article · Jun 2010 · Atherosclerosis Supplements

  • No preview · Article · Jun 2010 · Atherosclerosis Supplements