Platelets play a critical role in maintaining vascular integrity during inflammation, but little is known about the underlying molecular mechanisms. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation-induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a protocol for adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic (TP) mice. Unexpectedly, platelets with impaired GPCR signaling, a crucial component of platelet plug formation and hemostasis, were indistinguishable from WT platelets in their ability to prevent hemorrhage at sites of inflammation. In contrast, inhibition of GPVI or genetic deletion of Clec2, the only ITAM receptors expressed on mouse platelets, significantly reduced the ability of platelets to prevent inflammation-induced hemorrhage. Moreover, transfusion of platelets without ITAM receptor function or platelets lacking the adapter protein SLP-76 into TP mice had no significant effect on vascular integrity during inflammation. These results indicate that the control of vascular integrity is a major function of immune-type receptors in platelets, highlighting a potential clinical complication of novel antithrombotic agents directed toward the ITAM signaling pathway.
Platelets play a central role in primary hemostasis by forming aggregates that plug holes in injured vessels. Half a century ago, detailed studies of the microvasculature by electron microscopy revealed that under inflammatory conditions that do not induce major disruption to vascular structure, individual platelets are mobilized to the vessel wall, where they interact with leukocytes and appear to seal gaps that arise between endothelial cells. Recent developments in genetic engineering and intravital microscopy have allowed further molecular and temporal characterization of these events. Surprisingly, it turns out that platelets support the recruitment of leukocytes to sites of inflammation. In parallel, however, they exercise their hemostatic function by securing the integrity of inflamed blood vessels to prevent bleeding from sites of leukocyte infiltration. It thus appears that platelets not only serve in concert as building blocks of the hemostatic plug but also act individually as gatekeepers of the vascular wall to help preserve vascular integrity while coordinating host defense. Variants of this recently appreciated hemostatic function of platelets that we refer to as "inflammation-associated hemostasis" are engaged in different contexts in which the endothelium is challenged or dysfunctional. Although the distinguishing characteristics of these variants and the underlying mechanisms of inflammation-associated hemostasis remain to be fully elucidated, they can differ notably from those supporting thrombosis, thus presenting therapeutic opportunities.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.