Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis (original) (raw)
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Arteriosclerosis, thrombosis, and vascular biology, 2016
Beyond their eminent role in hemostasis and thrombosis, platelets are recognized as mediators of inflammation. Platelet cluster of differentiation 40 (CD40) ligand (CD40L and CD154) plays a key role in mediating platelet-induced inflammation in atherosclerosis. CD40, the receptor for CD40L, is present on platelets; however, the role of CD40 on this cell type is until now undefined. We found that in both mice and humans, platelet CD40 mediates the formation of platelet-leukocyte aggregates and the release of chemokine (C-X-C motif) ligand 4. Leukocytes were also less prone to adhere to CD40-deficient thrombi. However, platelet CD40 was not involved in platelet aggregation. Injection of activated platelets isolated from Cd40(-/-)Apoe(-/-) mice adhered less to the endothelium on injection into Apoe(-/-) mice when compared with CD40-sufficient platelets. Furthermore, lack of CD40 on injected platelets led to reduced leukocyte recruitment to the carotid artery as assayed by intravital mi...
The role of CD40/CD40 ligand system in the pathogenesis of atherosclerosis
Cardiology Journal, 2006
Increasing evidence shows that the cells associated with atherogenesis (platelets, endothelial and smooth muscle cells, fibroblasts, monocytes, macrophages and T lymphocytes) express proinflammatory pathways of CD40 signalling. Activation of platelets CD40/CD40L system and its counterpart CD40 receptors on vascular cell surface induces the expression of various adhesion molecules, cytokines, chemokines, growth factors, matrix metalloproteinases and reactive oxygen species, the substances which are responsible for plaque formation, destabilisation and rupture. Disturbed laminar blood flow (low wall shear stress) can mediate CD40/CD40L system signalling by increasing the residence time of the interaction between platelets and endothelium. Experimental studies provide considerable data indicating that interruption of CD40 signalling significantly inhibits the progression of established atheroma and altered plaque composition for a lipid-poor collagen-rich stable plaque phenotype. Recent data suggest different aspects of CD40/CD40L system activation in the context of risk factors (hypercholesterolaemia, diabetes mellitus, obesity and cigarette smoking) link them into the pro-inflammatory and prothrombotic milieu, aggravating the atherosclerotic process. Activation of the CD40/CD40L system plays a pivotal role in acute coronary syndromes as well as acute cerebral ischaemia. After percutaneous coronary intervention the risk of restenosis increases with high levels of plasma-soluble CD40L (sCD40L). In apparently healthy women sCD40L concentration has been recognised as an independent risk factor of the first acute coronary event. Clopidogrel, aspirin, statins and some oral hypoglycaemic agents share common anti-inflammatory properties including inhibition of CD40/CD40L intercellular signalling. To prevent plaque progression, destabilisation and thrombotic complications, anti-platelet treatment strategy should be focused on inhibition of platelet activation instead of on response to platelet aggregation. (Folia Cardiol. 2006; 13: 283-292) CD40/CD40L system, platelets, atherosclerosis Pro-inflammatory activities of the CD40/CD40L system Platelets are involved not only in homeostasis and thrombosis, but also, as is increasingly recognised, in atherosclerotic lesion formation and restenosis processes. "Some data indicate that at sites predisposed for atherosclerotic development like artery bifurcations, T-junctions, turbulent flow can induce endothelial overexpression of adhesion
Circulation, 2002
tudies focusing on cellular and molecular mechanisms that regulate atherosclerosis have fed scientific journals for decades, nearly as long as it takes an atherosclerotic plaque to grow, rupture, and eventually induce vascular occlusive events.
Blood, 2001
Recently, we have demonstrated that human platelets carry preformed CD40 ligand (CD154) molecules, which rapidly appear on the platelet surface following stimulation by thrombin. Once on the surface, platelet CD154 induces an inflammatory reaction of CD40-bearing endothelial cells. This study shows that strong platelet agonists other than thrombin also lead to the expression of CD154 on the platelet surface. At the same time, several lines of evidence are presented that together indicate that thrombotic events in the vasculature are generally accompanied by activation of the inflammatory potential of platelet CD154. This study also reports the constitutive expression of CD40, the receptor for CD154, on platelets. The binding of CD154 to coexpressed CD40 in the platelet aggregate leads within minutes to hours to the cleavage of membrane-bound surface CD154 and the release of an 18-kd soluble form of the molecule. Soluble CD154 (sCD154), in contrast to transmembrane CD154, can no long...
The role of the CD 40 / CD 40 ligand system in the pathogenesis of atherosclerosis
2006
Increasing evidence shows that the cells associated with atherogenesis (platelets, endothelial and smooth muscle cells, fibroblasts, monocytes, macrophages and T lymphocytes) express proinflammatory pathways of CD40 signalling. Activation of platelets CD40/CD40L system and its counterpart CD40 receptors on vascular cell surface induces the expression of various adhesion molecules, cytokines, chemokines, growth factors, matrix metalloproteinases and reactive oxygen species, the substances which are responsible for plaque formation, destabilisation and rupture. Disturbed laminar blood flow (low wall shear stress) can mediate CD40/CD40L system signalling by increasing the residence time of the interaction between platelets and endothelium. Experimental studies provide considerable data indicating that interruption of CD40 signalling significantly inhibits the progression of established atheroma and altered plaque composition for a lipid-poor collagen-rich stable plaque phenotype. Recen...
Arteriosclerosis, thrombosis, and vascular biology, 2015
To investigate the roles and signaling pathways of CD40L and CD40 in platelet-platelet interactions and thrombus formation under conditions relevant for atherothrombosis. Platelets from mice prone to atherosclerosis lacking CD40L (Cd40lg(-/-)Apoe(-/-)) showed diminished αIIbβ3 activation and α-granule secretion in response to glycoprotein VI stimulation, whereas these responses of CD40-deficient platelets (Cd40(-/-)Apoe(-/-)) were not decreased. Using blood from Cd40lg(-/-)Apoe(-/-) and Cd40(-/-)Apoe(-/-) mice, the glycoprotein VI-dependent formation of dense thrombi was impaired on atherosclerotic plaque material or on collagen, in comparison with Apoe(-/-) blood. In all genotypes, addition of CD40L to the blood enhanced the growth of dense thrombi on plaques and collagen. Similarly, CD40L enhanced glycoprotein VI-induced platelet aggregation, even with platelets deficient in CD40. This potentiation was antagonized in Pik3cb(R/R) platelets or by inhibiting phosphatidylinositol 3-ki...
CD40L stabilizes arterial thrombi by a β3 integrin–dependent mechanism
Nature Medicine, 2002
CD40L (also known as CD154 and gp39) is a transmembrane protein and member of the tumor necrosis factor (TNF) family. It is expressed on cells of the immune system (activated CD4 + T cells, mast cells, basophils, eosinophils and natural killer cells) 1 and on activated platelets 2. The receptor for CD40L, CD40, from the TNF receptor family, is widely distributed, primarily on cells of the vasculature. Several immune functions for CD40L have been reported; the most prominent is in isotype switching during the immune response. Mutations in the gene encoding CD40L lead to a human pathology termed X-linked hyper-immunoglobulin-M syndrome 3. Ligation of CD40 by CD40L also has a role in the pathogenesis of atherosclerosis 4. Although the etiology of these responses may result from immune deficiency, the inflammatory activity of CD40L on platelets and other cells within the vasculature has also been considered as CD40L induces the expression of chemokines (monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and IL-8), pro-inflammatory adhesion molecules (vascular cellular adhesion molecule-1, intracellular adhesion molecule-1 and P-selectin), and tissue factor (TF), and downregulates the expression of thrombomodulin in vascular cells 5-7. CD40L is shed from stimulated lymphocytes generating soluble CD40L (sCD40L), and is actively released following platelet stimulation 8 and during acute coronary thrombosis 9. A recent study shows that the proteolytic cleavage of CD40L from platelets is stimulated by its binding to CD40 which is expressed constitutively on platelets 8. Although a precise role for sCD40L remains to be determined, two activities have been observed. First, sCD40L in serum of individuals with acute coronary thrombotic syndromes has been shown to be pro-inflammatory. In addition, sCD40L may promote coagulation as it induces TF expression on monocytes 10,11 , similar to an activity of soluble Pselectin 12. Soluble P-selectin in plasma promotes coagulation by causing the formation of TF-containing microparticles 13 , and CD40L could have similar activity. sCD40L also contains a KGD sequence 14 , a known binding motif specific for α IIb β 3 (ref. 15), the major platelet integrin. In addition, antibodies against CD40L induce thrombotic events in primates and humans 16. Here we report a direct role for CD40L in high-shear platelet thrombosis that depends on a novel interaction of sCD40L with β 3 integrins in platelets. Instability of large CD40L-/thrombi in mesenteric arterioles Thrombus formation in ferric chloride (FeCl 3)-induced injury of mesenteric arterioles of CD40L-/mice was compared with that of wild-type mice using intravital microscopy 17,18. Arterioles of 60-100-µm diameter with a shear rate of approximately 1300 per second were used. There was no difference in either initial adhesion of single platelets (97 ± 26 per min in CD40L-/versus 101 ± 24 per min in wild-type mice) or in the times required for first thrombus growth in wild-type and CD40L-/mice (Fig. 1a). However, in CD40L-/mice, large thrombi frequently ruptured and embolized, an event rarely seen in wild-type vessels (Fig. 1b), leading to a delay in vessel occlusion (Fig. 1c). Histological examination of the thrombi formed showed lower platelet density in the absence of CD40L (Fig. 1d), which probably contributed to the fragility of the thrombi. Platelets express 600-1,000 copies of CD40L (data not shown) and platelet activation is known to cause release of soluble CD40L (refs. 8,9). Therefore we investigated whether the soluble form of CD40L (rsCD40L) could restore the normal thrombotic process in CD40L-/vessels. Infusion of 1.6 mg/kg of rsCD40L just