Functional significance of the platelet immune receptors GPVI and CLEC-2
Julie Rayes, … , Steve P. Watson, Bernhard Nieswandt
Julie Rayes, … , Steve P. Watson, Bernhard Nieswandt
Published January 2, 2019
Citation Information: J Clin Invest. 2019;129(1):12-23. https://doi.org/10.1172/JCI122955.
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Review

Functional significance of the platelet immune receptors GPVI and CLEC-2

Abstract

Although platelets are best known for their role in hemostasis, they are also crucial in development, host defense, inflammation, and tissue repair. Many of these roles are regulated by the immune-like receptors glycoprotein VI (GPVI) and C-type lectin receptor 2 (CLEC-2), which signal through an immunoreceptor tyrosine–based activation motif (ITAM). GPVI is activated by collagen in the subendothelial matrix, by fibrin and fibrinogen in the thrombus, and by a remarkable number of other ligands. CLEC-2 is activated by the transmembrane protein podoplanin, which is found outside of the vasculature and is upregulated in development, inflammation, and cancer, but there is also evidence for additional ligands. In this Review, we discuss the physiological and pathological roles of CLEC-2 and GPVI and their potential as targets in thrombosis and thrombo-inflammatory disorders (i.e., disorders in which inflammation plays a critical role in the ensuing thrombosis) relative to current antiplatelet drugs.

Authors

Julie Rayes, Steve P. Watson, Bernhard Nieswandt

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Figure 3

Multiple roles of CLEC-2 and GPVI in thrombo-inflammation and thrombosis.

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Multiple roles of CLEC-2 and GPVI in thrombo-inflammation and thrombosis...
During thrombo-inflammatory diseases, platelets regulate immune cell recruitment at the site of inflammation. Deletion of GPVI (Gp6–/–) decreases the inflammatory reaction as a consequence of a reduction in neutrophil recruitment and the number of inflammatory macrophages. Conversely, deletion of CLEC2 (Clec1b–/–) potentiates the inflammatory reaction through an increase in neutrophil infiltration and inducing a proinflammatory macrophage phenotype. In addition, GPVI promotes the underlying inflammation that drives plaque formation and drives thrombus formation upon plaque rupture. During venous thrombosis, CLEC-2 promotes thrombosis at sites of breach in the vessel wall by upregulating podoplanin on stromal cells and inflammatory macrophages.