The Involvement of Toll-like Receptor-2 in Arterial Thrombus Formation

 

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Abstract

There is emerging evidence for the participation of toll-like receptor-2 (TLR2) expressed on platelets and endothelial cells in the setting of arterial thrombosis. In isolated human platelets, TLR2/1 activation was demonstrated to induce platelet activation, secretion, aggregation, adhesion to collagen coatings and the formation of platelet–leukocyte conjugates, whereas murine platelets were less sensitive to TLR2/1 stimulation. Also, endothelial cells can be activated by stimulation with TLR2 agonists, resulting in increased expression of adhesion molecules, synthesis of inflammatory mediators and Weibel–Palade body exocytosis. Endothelial TLR2 signalling promotes atherosclerotic lesion development in mouse atherosclerosis models. Experiments with germ-free mouse models demonstrated that the presence of commensal microbiota increased endothelial von Willebrand factor synthesis in the liver through TLR2. In the carotid artery ligation model, the elevated von Willebrand factor plasma levels enhanced platelet deposition to the injury site. Furthermore, in the hyperlipidemic ApoE-deficient mouse model, TLR2 deficiency was shown to protect from ferric chloride–induced carotid artery thrombosis. This review article provides an overview on TLR2 signalling in platelets and the vascular endothelium and summarizes how TLR2 signalling contributes to arterial thrombosis.

Zusammenfassung

Es gibt neue Hinweise für die Beteiligung von Toll-like-Rezeptor-2 (TLR2) auf Thrombozyten und Endothelzellen, in der arteriellen Thrombose. In isolierten menschlichen Blutplättchen wurde gezeigt, dass die TLR2/1-Aktivierung die Plättchenaktivierung, Sekretion, Aggregation, Adhäsion an Kollagenbeschichtungen und die Bildung von Thrombozyten-Leukozyten-Konjugaten induziert, während Mausplättchen weniger empfindlich auf TLR2/1-Stimulation reagieren. Endothelzellen können ebenfalls durch Stimulation mit TLR2-Agonisten aktiviert werden, was zu einer erhöhten Expression von Adhäsionsmolekülen, Synthese von Entzündungsmediatoren und Weibel-Palade-Körper-Exozytose führt. Endotheliale TLR2-Signalgebung fördert die Entwicklung atherosklerotischer Läsionen in Maus-Atherosklerosemodell. Experimente mit keimfreien Mausmodellen zeigen, dass das Vorhandensein von kommensalen Mikrobiota die endotheliale von Willebrand-Faktor-Synthese in der Leber durch TLR2 erhöhen kann. Im Ligationsmodell der Karotisarterie förderte der erhöhte von-Willebrand-Faktor-Plasmaspiegel die Thrombozytenablagerung an die Verletzungsstelle. Darüber hinaus wurde gezeigt, dass der TLR2-Mangel im Hyperlipidämie-ApoE-defizienten Mausmodell vor Eisenchlorid-induzierter Karotisarterienthrombose schützt. Dieser Übersichtsartikel beschreibt die TLR2-Signaltransduktion in Thrombozyten und im vaskulären Endothel und fasst zusammen, wie der TLR2-Signalweg zur arteriellen Thrombose beiträgt.

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