The signaling role of CD40 ligand in platelet biology and in platelet component transfusion (original) (raw)
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Lack of evidence of CD40 ligand involvement in transfusion-related acute lung injury
Clinical & Experimental Immunology, 2011
Activated platelets have been implicated in playing a major role in transfusion-related acute lung injury (TRALI), as platelets can trigger neutrophils, resulting in vascular damage. We hypothesized that binding of platelet CD40 ligand (CD40L) to endothelial CD40 is essential in the onset of TRALI. Mice were challenged with monoclonal major histocompatibility complex (MHC)-1 antibody which induced TRALI, evidenced by pulmonary oedema, accompanied by significantly elevated bronchoalveolar fluid (BALF) levels of total protein and elevated plasma levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) compared to infusion of isotype antibody (all Ps < 0·05). Treatment with ciglitazone, which inhibits platelet CD40L expression, had no effect on pulmonary and systemic inflammation compared to controls. In addition, treatment with anti-CD40L antibody, which antagonizes all CD40-CD40L interactions, also did not abrogate the TRALI reaction. Furthermore, levels of soluble CD40L were measured in a cohort of cardiac surgery patients, who were followed prospectively for the onset of TRALI after transfusion. Plasma levels of sCD40L at baseline and at time of developing TRALI did not differ between TRALI patients and controls (transfused cardiac surgery patients not developing acute lung injury) (275 Ϯ 192 versus 258 Ϯ 346 and 93 Ϯ 82 versus 93 Ϯ 123 pg/ml, respectively, not significant). In conclusion, these results do not support the idea that the CD40-CD40L interaction is involved in mediating TRALI.
Neutrophil CD40 enhances platelet-mediated inflammation
Thrombosis …, 2008
INTRODUCTION: CD40 is a transmembrane protein expressed on monocytes, macrophages, endothelial cells, and platelets. Platelets are the richest source of soluble CD40 ligand (sCD40L) and interact with monocytes and endothelial cells via CD40. While ...
CD40 Ligand Influences Platelet Release of Reactive Oxygen Intermediates
2010
Objective-Soluble CD40 ligand (sCD40L) has been recently implicated in the pathogenesis of atherosclerosis. Elevated levels of sCD40L in acute coronary syndrome patients suggests enhanced platelet function; however, the exact mechanism by which this occurs is unknown. In this study, we examined the effect of sCD40L on platelet function and reactive oxygen and nitrogen species (RONS) generation. Methods and Results-Platelet stimulation in the presence of recombinant sCD40L (rsCD40L) led to enhanced generation of RONS as measured by DCFHDA oxidation and confocal microscopy. Incubation with rsCD40L led to enhanced platelet P-selectin expression, aggregation, and platelet-leukocyte conjugation. Platelets isolated from CD40L-deficient mice had decreased agonist-induced NO release as compared with wild-type mice. Incubation of platelets with rsCD40L enhanced stimulation-induced p38 MAP kinase and Akt phosphorylation. Conclusion-Soluble CD40L enhances platelet activation, aggregation, and platelet-leukocyte conjugation, as well as increases stimulation-induced platelet release of RONS through activation of Akt and p38 MAP kinase signaling pathways. These data suggest that sCD40L regulates platelet-dependent inflammatory and thrombotic responses that contribute to the pathogenesis of atherothrombosis. (Arterioscler Thromb Vasc Biol. 2005;25:0-0.)
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...
Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis
Blood, 2010
atherosclerosis Platelet CD40L mediates thrombotic and inflammatory processes in http://bloodjournal.hematologylibrary.org/content/116/20/4317.full.html Updated information and services can be found at: (433 articles) Thrombosis and Hemostasis (261 articles) Platelets and Thrombopoiesis (4733 articles) Immunobiology Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests
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.
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...
Involvement of nuclear factor κB in platelet CD40 signaling
Biochemical and Biophysical Research Communications, 2012
a b s t r a c t CD40 ligand (CD40L) is a thrombo-inflammatory molecule that predicts cardiovascular events. Platelets constitute the major source of soluble CD40L (sCD40L), which has been shown to potentiate platelet activation and aggregation, in a CD40-dependent manner, via p38 mitogen activated protein kinase (MAPK) and Rac1 signaling. In many cells, the CD40L/CD40 dyad also induces activation of nuclear factor kappa B (NF-jB). Given that platelets contain NF-jB, we hypothesized that it may be involved in platelet CD40 signaling and function. In human platelets, sCD40L induces association of CD40 with its adaptor protein the tumor necrosis factor receptor associated factor 2 and triggers phosphorylation of IjBa, which are abolished by CD40L blockade. Inhibition of IjBa phosphorylation reverses sCD40L-induced IjBa phosphorylation without affecting p38 MAPK phosphorylation. On the other hand, inhibition of p38 MAPK phosphorylation has no effect on IjBa phosphorylation, indicating a divergence in the signaling pathway originating from CD40 upon its ligation. In functional studies, inhibition of IjBa phosphorylation reverses sCD40L-induced platelet activation and potentiation of platelet aggregation in response to a sub-threshold concentration of collagen. This study demonstrates that the sCD40L/CD40 axis triggers NF-jB activation in platelets. This signaling pathway plays a critical role in platelet activation and aggregation upon sCD40L stimulation and may represent an important target against thrombo-inflammatory disorders.