Platelets in inflammation: regulation of leukocyte activities and vascular repair

Abstract

There is now a large body of evidence that platelets are central actors of inflammatory reactions. Indeed, platelets play a significant role in a variety of inflammatory diseases. These diseases include conditions as varied as atherosclerosis, arthritis, dermatitis, glomerulonephritis, or acute lung injury. In this context, one can note that inflammation is a convenient but imprecise catch-all term that is used to cover a wide range of situations. Therefore, when discussing the role of platelets in inflammation, it is important to clearly define the pathophysiological context and the exact stage of the reaction. Inflammatory reactions are indeed multistep processes that can be either acute or chronic, and their sequence can vary greatly depending on the situation and organ concerned. Here, we focus on how platelets contribute to inflammatory reactions involving recruitment of neutrophils and/or macrophages. Specifically, we review past and recent data showing that platelets intervene at various stages of these reactions to regulate parameters such as endothelial permeability, the recruitment of neutrophils and macrophages and their effector functions, as well as inflammatory bleeding. The mechanisms underlying these various modulating effect of platelets are also discussed.

Keywords: ITAM; bleeding; inflammation; monocytes; neutrophils; platelets; thrombocytopenia; vascular permeability.

Figure 1

Platelets are integral players of inflammatory reactions. (A) During the early phase of inflammatory reactions, platelets are recruited to inflamed vessels and enhance vascular permeability by secreting pro-permeability factors such as serotonin, vascular endothelial growth factor A (VEGF-A), or platelet-activating factor (PAF). Platelets further enhance the recruitment and infiltration of leukocytes by secreting chemokines [e.g., activation or normal T cell expressed and secreted (RANTES) or platelet factor 4 (PF-4)], and by upregulating the expression and/or activation of adhesion molecules on leukocytes and endothelial cells via direct cell–cell contacts and secretion of pro-inflammatory cytokines. The platelet receptors (e.g., GPVI, GPIb, GPIIbIIIa, or P-selectin) supporting the interactions of platelets with inflamed vessels and/or leukocytes vary with the organ and inflammatory reactions concerned. (B) Platelets can modulate various leukocyte effector functions: toll-like receptor 4 (TLR4)-dependent activation of platelets promotes the formation of antibacterial neutrophil extracellular traps (NETs); platelets can also either stimulate or inhibit the production of reactive oxygen species (ROS) and/or secretion of cytokines and cytotoxic enzymes [e.g., myeloperoxidase (MPO), serine proteases] by neutrophils and macrophages depending on the inflammatory situation; platelets can stimulate phagocytosis and thus enhance foam cell formation by promoting the uptake of oxidized low-density lipoprotein by monocytes/macrophages (oxLDL). (C) Platelets prevent bleeding associated with leukocyte trafficking. This protective action of platelets has been shown to be independent of thrombus formation and to rely on the engagement of platelet ITAM receptors, which might cause secretion of anti-permeability factors such as angiopoietin-1 (Ang1) and sphingosine-1-phosphate (S1P) by platelets.