von Willebrand Factor and Platelet Glycoprotein Ib: A Thromboinflammatory Axis in Stroke

Denorme, Frederik; Vanhoorelbeke, Karen; Meyer, Simon F. De

doi:10.3389/fimmu.2019.02884

Cited by 82 publications

(69 citation statements)

References 91 publications

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“…Second, we propose that the neutrophil involvement in thrombus formation is dependent on plasma proteins (fibrinogen and vWF) ( Fig. 5A-F (52). However, the exact mechanism of granulocyte crawling on collagen has to be the object of further studies.…”

Section: Discussionmentioning

confidence: 89%

Ex vivoobservation of granulocyte activity during thrombus formation

Martyanov

et al. 2020

Preprint

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Infiltration of growing thrombi by leukocytes, being the key part of the thromboinflammation, is well established in vivo. The study was aimed at the development of an ex vivo simulation of this phenomenon. Thrombus 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 CD66b-positive cells (granulocytes) were observed in hirudinated or recalcified blood under low wall shear rate conditions (<200 s−1). These cells crawled around thrombi in a step-wise manner with an average rate of 70 nm/s. Pre-incubation of blood with leukocyte priming agents lead to a significant increase in average cell velocity. On the contrary, leukocytes from Wiskott-Aldrich syndrome patients demonstrated a 1.5-fold lower average velocity, in line with their impaired actin polymerization.Thereby, the observed features of granulocytes crawling are consistent with the neutrophil chemotaxis phenomenon. We conclude that the proposed ex vivo experimental setting allows us to observe granulocytes activity in near-physiological conditions.

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Section: Discussionmentioning

confidence: 89%

Ex vivoobservation of granulocyte activity during thrombus formation

Martyanov

et al. 2020

Preprint

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“…Thrombo-inflammation is the complex interplay between thrombosis and inflammation that can result in acute organ damage [1][2][3]. The process is best characterized in mouse models of ischaemic stroke and venous thrombosis.…”

Section: Introductionmentioning

confidence: 99%

“…The process is best characterized in mouse models of ischaemic stroke and venous thrombosis. Central to thrombo-inflammation is the release of ultra-large adhesive strings of von Willebrand factor (VWF) from activated endothelial cells, in response to inflammatory mediators such as interleukin-1 (IL-1), IL-6, tumour necrosis factor α, thrombin, or histamine [2]. A proportion of the VWF strings remain attached to the endothelial cell surface and recruit platelets and leukocytes.…”

Section: Introductionmentioning

confidence: 99%

“…Leukocytes similarly roll on VWF using their PSGL-1 receptor followed by stable adhesion via β2 integrins. Alternatively, leukocytes may be captured indirectly by platelets via interactions with platelet GPIb-IX-V or P-selectin [2]. In addition, monocytes can bind to VWF having first bound platelet-derived GPIb-IX-V-positive extracellular vesicles [4].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, monocytes can bind to VWF having first bound platelet-derived GPIb-IX-V-positive extracellular vesicles [4]. Together, platelet and leukocyte recruitment lead to further recruitment of inflammatory cells, platelet aggregation, and blockage of vessels causing organ damage [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

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Tspan18 is a novel regulator of thrombo-inflammation

Gavin

Koo

Tomlinson

2020

Med Microbiol Immunol

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The interplay between thrombosis and inflammation, termed thrombo-inflammation, causes acute organ damage in diseases such as ischaemic stroke and venous thrombosis. We have recently identified tetraspanin Tspan18 as a novel regulator of thrombo-inflammation. The tetraspanins are a family of 33 membrane proteins in humans that regulate the trafficking, clustering, and membrane diffusion of specific partner proteins. Tspan18 partners with the store-operated Ca 2+ entry channel Orai1 on endothelial cells. Orai1 appears to be expressed in all cells and is critical in health and disease. Orai1 mutations cause human immunodeficiency, resulting in chronic and often lethal infections, while Orai1-knockout mice die at around the time of birth. Orai1 is a promising drug target in autoimmune and inflammatory diseases, and Orai1 inhibitors are in clinical trials. The focus of this review is our work on Tspan18 and Orai1 in Tspan18-knockout mice and Tspan18-knockdown primary human endothelial cells. Orai1 trafficking to the cell surface is partially impaired in the absence of Tspan18, resulting in impaired Ca 2+ signaling and impaired release of the thrombo-inflammatory mediator von Willebrand factor following endothelial stimulation. As a consequence, Tspan18-knockout mice are protected in ischemia-reperfusion and deep vein thrombosis models. We provide new evidence that Tspan18 is relatively highly expressed in endothelial cells, through the analysis of publicly available single-cell transcriptomic data. We also present new data, showing that Tspan18 is required for normal Ca 2+ signaling in platelets, but the functional consequences are subtle and restricted to mildly defective platelet aggregation and spreading induced by the platelet collagen receptor GPVI. Finally, we generate structural models of human Tspan18 and Orai1 and hypothesize that Tspan18 regulates Orai1 Ca 2+ channel function at the cell surface by promoting its clustering.

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