Novel mechanisms of thrombo-inflammation during infection: spotlight on neutrophil extracellular trap-mediated platelet activation

Martina Colicchia, Gina Perrella, Poppy Gant, Julie Rayes, Martina Colicchia, Gina Perrella, Poppy Gant, Julie Rayes

Abstract

A state-of-the-art lecture titled "novel mechanisms of thrombo-inflammation during infection" was presented at the ISTH Congress in 2022. Platelet, neutrophil, and endothelial cell activation coordinate the development, progression, and resolution of thrombo-inflammatory events during infection. Activated platelets and neutrophil extracellular traps (NETs) are frequently observed in patients with sepsis and COVID-19, and high levels of NET-derived damage-associated molecular patterns (DAMPs) correlate with thrombotic complications. NET-associated DAMPs induce direct and indirect platelet activation, which in return potentiates neutrophil activation and NET formation. These coordinated interactions involve multiple receptors and signaling pathways contributing to vascular and organ damage exacerbating disease severity. This state-of-the-art review describes the main mechanisms by which platelets support NETosis and the key mechanisms by which NET-derived DAMPs trigger platelet activation and the formation of procoagulant platelets leading to thrombosis. We report how these DAMPs act through multiple receptors and signaling pathways differentially regulating cell activation and disease outcome, focusing on histones and S100A8/A9 and their contribution to the pathogenesis of sepsis and COVID-19. We further discuss the complexity of platelet activation during NETosis and the potential benefit of targeting selective or multiple NET-associated DAMPs to limit thrombo-inflammation during infection. Finally, we summarize relevant new data on this topic presented during the 2022 ISTH Congress.

Keywords: DAMPs; NETosis; S100A8/A9; histones; platelets.

© 2023 Published by Elsevier Inc.

Figures

Figure
Figure
Effect of NET-associated DAMPs on platelet activation. Platelet activation by pathogens or classical agonists induces platelet activation and supports platelet-dependent NETosis. Distinct receptors are involved in mice and humans and in response to different agonists in vitro, under flow conditions and in vivo. CD62P is a key driver of NETosis in mice in vitro and in vivo but not in humans in vitro. CD62P contributes to platelet-dependent vital NETosis in LPS-stimulated human platelets. Platelet HMGB1 supports NETosis through RAGE in humans and mice. GPIIb/IIIa mediates NETosis through MAC-1 in mice, whereas under flow conditions, VWF-GPIbα priming of human platelets triggers GPIIb/IIIa-dependent NETosis through SLC44A2. Platelet secretion of PF4, TxA2, RANTES, and VWF also contributes to NETosis. Multiple NET-associated DAMPs trigger platelet activation and the release of proinflammatory molecules. Cathepsin G induces platelet aggregation, and this effect is amplified by neutrophil elastase. Histones, in particular H3 and H4, induce platelet aggregation alongside with the formation of procoagulant platelets and thrombin generation, mainly through TLR2/TLR4. S100A8/A9 supports the formation of procoagulant platelets through a mechanism involving GPIb-IX-V and induces platelet pyroptosis through TLR4 with the subsequent release of oxidized mitochondrial DNA (ox-mtDNA) supporting NETosis and amplifying thrombo-inflammation.

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