Platelet-derived LIGHT induces inflammatory responses in endothelial cells and monocytes

Abstract

Traditionally, platelets are known to play an important role in hemostasis, thrombosis, and wound healing, but increasing evidence suggests that activated platelets also may promote inflammation. Platelet-induced modulation of inflammation seems to involve platelet expression of ligands in the tumor necrosis factor (TNF) superfamily such as CD40 ligand and Fas ligand. The present study demonstrates that LIGHT, another member of the TNF superfamily, is associated with platelets and is released as a soluble ligand on platelet activation. The release of LIGHT involves GP IIb/IIIa-dependent mechanisms and action of metal-dependent proteases as well as intracellular processes such as actin polymerization. We also report that platelet-derived LIGHT is biologically active and can induce an inflammatory response in monocytes and particularly within endothelial cells measured as up-regulation of adhesion molecules and release of chemokines. Moreover, we demonstrate that thrombus material, obtained at the site of plaque rupture in patients with acute myocardial infarction, contains platelet-associated LIGHT, suggesting that LIGHT-mediated inflammation also is operating in vivo within an inflamed and thrombotic vessel wall. The data may suggest a pathogenic role for platelet-derived LIGHT in atherogenesis and plaque destabilization as well as in other inflammatory disorders involving leukocyte infiltration into the vessel wall. IntroductionThe traditional role of platelets as mediators of hemostasis and thrombosis is well documented. Increasing evidence suggests that activated platelets also play a key role in inflammation. Hence, on activation platelets release and express inflammatory mediators, induce an inflammatory response in adjacent leukocytes and endothelial cells, and respond with activation to several of the mediators produced by these cells. [1][2][3][4][5][6] Such interactions between platelets and leukocytes/endothelial cells seem to play a pathogenic role in atherosclerosis as well as in other immune-mediated disorders.Several platelet-derived mediators, such as chemokines and prostaglandins, appear to be involved in platelet-mediated inflammation. 1 Recently, much attention has been focused on the role of platelet-associated CD40 ligand (CD40L), a ligand in the tumor necrosis factor (TNF) superfamily, in this inflammatory loop between platelets and other cells. Thus, platelet-associated CD40L may interact with CD40, which is constitutively expressed on a wide range of cells, such as macrophages, endothelial cells, and vascular smooth muscle cells, resulting in various inflammatory responses. 7,8 Moreover, platelet-derived FasL, another member of the TNF superfamily, was recently shown to induce apoptosis in Fas ϩ tumor cells, further suggesting a role for ligands of this cytokine superfamily in platelet-mediated immune responses. 9 LIGHT, the name of which is derived from "homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus (HSV) glycoprotein D for herpes virus...

Increased expression of LIGHT/TNFSF14 and its receptors in experimental and clinical heart failure☆

“…Our findings in experimental HF suggest that this receptor can also be expressed in cardiomyocytes, with particularly high expression in the failing myocardium. LIGHT has been reported to promote several effects relevant to HF, such as production of inflammatory cytokines, matrix degradation, and increased production of reactive oxygen species in leukocytes, endothelial cells, and fibroblasts [13,16,22]; some of these effects seem to involve LIGHT-HVEM interaction. Furthermore, studies in animal models suggest that LIGHT-HVEM interaction may play a major role in inflammatory bowel disease, allograft rejection, and graft-versus-host disease [9].…”

“…Primary human umbilical vein endothelial cells (HUVECs) were obtained from umbilical cord veins, cultured as described elsewhere [16], and stimulated with different concentrations of rhLIGHT (R&D Systems). At different time points, cell-free supernatants (PBMC and HUVEC) and cell pellets (HUVEC) were harvested and stored at − 80°C.…”

GITR Ligand Provided by Thrombopoietic Cells Inhibits NK Cell Antitumor Activity

“…Previous data show expression of several TNF family members on platelets (25)(26)(27)(28)(29)(30)(31)(32)(33). In this study we set out to determine whether GITRL was expressed upon in vitro differentiation of megakaryocytes from CD34 + stem cells.…”

Platelet-vessel wall interactions in atherosclerotic disease

“…ReleaseofplateletderivedCD40L,which is stored in high amounts in plateletgranules and released within seconds after activation in vitro,induces inflammatoryr esponses in endothelium (9). Ligation of CD40 on endothelialcells (ECs) by CD40Lexpressed on the surfaceof activatedplatelets increased the releaseofinterleukin (IL)-8and monocyte chemoattractant protein 1(MCP-1), major chemoattractantsf or neutrophils and monocytes (9).O nlyr ecently,t he expression of LIGHT (TNFSF1 4, ap rotein,w hich belongs to the tumor necrosis factor super-familya nd causes pro-inflammatoryand pro-thromboticchangesqualitatively comparable to effectsofCD40 ligand) wasidentified on platelets upon exposure to ADP or TRAP-1 (10,11). Platelet-associatedLIGHT influenced adhesion of platelets to the endothelium, while soluble LIGHT inducedapro-inflammatory state in vascularECs, rendering this moleculeapotential therapeutic or diagnostic target in atherosclerosis (11).Asp atients with myocardiali nfarction revealed increased levels of solubleLIGHT,this molecule may be of clinicalimportancefor the pathogenesis of coronaryartery disease ( 11).…”