Platelets: New Bricks in the Building of Neutrophil Extracellular Traps

Abstract

In addition to being key elements in hemostasis and thrombosis, platelets have an important role in the inflammatory and innate immune response. This activity is associated with their capability to recognize pathogens through the expression of toll-like receptors, the secretion of various cytokines, chemokines, and growth factors stored within their granules, and the expression of cell adhesion molecules that allows interaction with other immune cells, mainly neutrophils and monocytes. As part of the first line of defense, neutrophils control invading pathogens by phagocytosis, the release of antimicrobial proteins during degranulation, or through the formation of web-like structures named neutrophil extracellular traps (NETs). NETs are formed by chromatin, proteases, and antimicrobial proteins, and their main function is to trap and kill bacteria, virus, and fungi, avoiding their dissemination. Besides microorganisms, NET formation is also triggered by proinflammatory molecules and platelets. The uncontrolled formation of NETs might exert tissue damage and has been involved in a pathogenic mechanism of autoimmune and prothrombotic clinical conditions. In this review, we discuss the role of platelets in NET generation highlighting the mediators, stimuli, and molecular mechanisms involved in this phenomenon, both in human and murine models.

Keywords: inflammation; neutrophil extracellular traps; neutrophils; platelets; platelet–neutrophil interaction.

Figure 1

Known molecules involved in platelet-mediated NET formation. In humans (left), platelet activation induces thromboxane A₂ (TXA₂) formation, which triggers the release of high mobility group box 1 (HMGB1), von Willebrand factor (vWF), and platelet factor 4 (PF4). vWF binds to its platelet receptor, glycoprotein (GP)Ib, which binds to CD18 in neutrophils. PF4 and HMGB1 act directly upon neutrophils and induce DNA release. In mice, not only TXA₂ generation and HMGB1 are involved but also PF4 and RANTES, through GPCR, induce platelet-mediated NET formation. Also, the interaction between P-selectin-PSGL-1 and α_IIbβ₃-Mac-1 is required for the release of NETs.

Figure 2

Signaling pathways involved in platelet-mediated NET formation. NETosis mediated by platelets requires activation of both human platelet and neutrophils ERK and Src kinases. In addition, PI3K signaling pathway in neutrophils is also required for NET formation. While NADPH oxidase in neutrophils is necessary to induce NET formation in mice, the signaling pathways in platelets are still not identified.