Beyond Hemostasis: Platelet Innate Immune Interactions and Thromboinflammation

Abstract

There is accumulating evidence that platelets play roles beyond their traditional functions in thrombosis and hemostasis, e.g., in inflammatory processes, infection and cancer, and that they interact, stimulate and regulate cells of the innate immune system such as neutrophils, monocytes and macrophages. In this review, we will focus on platelet activation in hemostatic and inflammatory processes, as well as platelet interactions with neutrophils and monocytes/macrophages. We take a closer look at the contributions of major platelet receptors GPIb, α_IIbβ₃, TLT-1, CLEC-2 and Toll-like receptors (TLRs) as well as secretions from platelet granules on platelet-neutrophil aggregate and neutrophil extracellular trap (NET) formation in atherosclerosis, transfusion-related acute lung injury (TRALI) and COVID-19. Further, we will address platelet-monocyte and macrophage interactions during cancer metastasis, infection, sepsis and platelet clearance.

Keywords: COVID-19; NETs; atherosclerosis; cancer; hemostasis; inflammation; macrophages; monocytes; neutrophils; platelets; thrombosis.

Figure 1

Mechanisms of platelet–neutrophil complex formation. Upon endothelial cell disruption, platelets and neutrophils become activated due to exposure to collagen and activated endothelial cells. Platelet activation results in P-selectin exposure and subsequent neutrophil activation via P-selectin–PSGL1 interaction. Neutrophil activation is further enhanced upon platelet granule content release (CXCL4, CXCL7, CXCL1, HMGB1). The synergistic activation of neutrophils by all these agents via Mac-1, PSGL-1, SLC44A2 and CD40 receptors eventually results in platelet–neutrophil complexes and neutrophil DNA-trap secretion—NETosis. NETs contain the proteases cathepsin G, neutrophil elastase and myeloperoxidase, which can both activate platelets and the coagulation cascade. Multiple positive feedback loops are present at all levels of this system and, thus, both platelet and neutrophils become involved in immunothrombosis and subsequent thromboinflammation. Cell activation is shown by yellow lightnings. Dotted lines represent interactions of soluble mediators and receptors. NET—neutrophil extracellular trap, PNC—platelet–neutrophil complex, Plt—platelet, Neu—neutrophil.

Figure 2

Platelet–monocyte interactions and platelet–monocyte complex (PMC) formation. Several factors such as bacterial or viral infection (1) can contribute to the activation of both platelets and monocytes (2). Once activated, platelets and monocytes can interact directly through receptors expressed on their surface, and soluble factors released from platelets can further modulate monocyte activity (3). This interaction can lead monocytes to extravasate and differentiate towards macrophages (4a) or alternatively lead to platelet–monocyte complex formation (4b). Cell activation is shown by yellow lightnings. Plt—platelet, Mon—monocyte, PMC—platelet–monocyte complex.