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Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo.

ABSTRACT: The integrin family is composed of a series of 24 ?? heterodimer transmembrane adhesion receptors that mediate cell-cell and cell-extracellular matrix interactions. Adaptor molecules bearing immunoreceptor tyrosine-based activation motifs (ITAMs) have recently been shown to cooperate with specific integrins to increase the efficiency of transmitting ligand-binding-induced signals into cells. In human platelets, Fc receptor ?-chain IIa (Fc?RIIa) has been identified as an ITAM-bearing transmembrane receptor responsible for mediating "outside-in" signaling through ?IIb?3, the major adhesion receptor on the platelet surface. To explore the importance of Fc?RIIa in thrombosis and hemostasis, we subjected Fc?RIIa-negative and Fc?RIIa-positive murine platelets to a number of well-accepted models of platelet function. Compared with their Fc?RIIa-negative counterparts, Fc?RIIa-positive platelets exhibited increased tyrosine phosphorylation of Syk and phospholipase C?2 and increased spreading upon interaction with immobilized fibrinogen, retracted a fibrin clot faster, and showed markedly enhanced thrombus formation when perfused over a collagen-coated flow chamber under conditions of arterial and venous shear. They also displayed increased thrombus formation and fibrin deposition in in vivo models of vascular injury. Taken together, these data establish Fc?RIIa as a physiologically important functional conduit for ?IIb?3-mediated outside-in signaling, and suggest that modulating the activity of this novel integrin/ITAM pair might be effective in controlling thrombosis.

SUBMITTER: Zhi H

PROVIDER: S-EPMC3591804 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo.

Zhi Huiying H Rauova Lubica L Hayes Vincent V Gao Cunji C Boylan Brian B Newman Debra K DK McKenzie Steven E SE Cooley Brian C BC Poncz Mortimer M Newman Peter J PJ

Blood 20121220 10

The integrin family is composed of a series of 24 αβ heterodimer transmembrane adhesion receptors that mediate cell-cell and cell-extracellular matrix interactions. Adaptor molecules bearing immunoreceptor tyrosine-based activation motifs (ITAMs) have recently been shown to cooperate with specific integrins to increase the efficiency of transmitting ligand-binding-induced signals into cells. In human platelets, Fc receptor γ-chain IIa (FcγRIIa) has been identified as an ITAM-bearing transmembran ...[more]

PMID: 23264598

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Project description:BackgroundThe process of thrombus formation is thought to involve interactions between platelets and leukocytes. Leukocyte incorporation into growing thrombi has been well established in vivo, and a number of properties of platelet-leukocyte interactions critical for thrombus formation have been characterized in vitro in thromboinflammatory settings and have clinical relevance. Leukocyte activity can be impaired in distinct hereditary and acquired disorders of immunological nature, among which is Wiskott-Aldrich Syndrome (WAS). However, a more quantitative characterization of leukocyte behavior in thromboinflammatory conditions has been hampered by lack of approaches for its study ex vivo. Here, we aimed to develop an ex vivo model of thromboinflammation, and compared granulocyte behavior of WAS patients and healthy donors.ResultsThrombus formation in anticoagulated whole blood from healthy volunteers and patients was visualized by fluorescent microscopy in parallel-plate flow chambers with fibrillar collagen type I coverslips. Moving granulocytes were observed in hirudinated or sodium citrate-recalcified blood under low wall shear rate conditions (100 s-1). These cells crawled around thrombi in a step-wise manner with an average velocity of 90-120 nm/s. Pre-incubation of blood with granulocyte priming agents lead to a significant decrease in mean-velocity of the cells and increase in the number of adherent cells. The leukocytes from patients with WAS demonstrated a 1.5-fold lower mean velocity, in line with their impaired actin polymerization. It is noteworthy that in an experimental setting where patients' platelets were replaced with healthy donor's platelets the granulocytes' crawling velocity did not change, thus proving that WASP (WAS protein) deficiency causes disruption of granulocytes' behavior. Thereby, the observed features of granulocytes crawling are consistent with the neutrophil chemotaxis phenomenon. As most of the crawling granulocytes carried procoagulant platelets teared from thrombi, we propose that the role of granulocytes in thrombus formation is that of platelet scavengers.ConclusionsWe have developed an ex vivo experimental model applicable for observation of granulocyte activity in thrombus formation. Using the proposed setting, we observed a reduction of motility of granulocytes of patients with WAS. We suggest that our ex vivo approach should be useful both for basic and for clinical research.

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Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo.

Publications

Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo.

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