Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis

Abstract

Platelets, non-nucleated blood components first described over 130 years ago, are recognized as the primary cell regulating hemostasis and thrombosis. The vascular importance of platelets has been attributed to their essential role in thrombosis, mediating myocardial infarction, stroke, and venous thromboembolism. Increasing knowledge on the platelets' role in the vasculature has led to many advances in understanding not only how platelets interact with the vessel wall but also how they convey changes in the environment to other circulating cells. In addition to their well-described hemostatic function, platelets are active participants in the immune response to microbial organisms and foreign substances. Although incompletely understood, the immune role of platelets is a delicate balance between its pathogenic response and its regulation of thrombotic and hemostatic functions. Platelets mediate complex vascular homeostasis via specific receptors and granule release, RNA transfer, and mitochondrial secretion that subsequently regulates hemostasis and thrombosis, infection, and innate and adaptive immunity.

Keywords: blood platelets; communication; hemostasis; immunity; infection; thrombosis.

Figure 1. Differences in platelet thrombotic vs. immune activation visualized by scanning electron microscopy

Isolated A. human platelets or B. human platelets mixed with leukocytes, were treated with immune (Loxoribine-Loxo, Encephalomyocarditis virus-EMCV) or thrombotic agonists. Panels demonstrate differing levels of activation when platelets are activated via immune vs. thrombotic pathways.

Figure 2. Platelet-mediated interactions with vascular or circulating cells

Platelets interact with endothelial and immune cells in the circulation, orchestrating a response to microbes, inflammatory stimuli and vessel damage. Through their TLRs (or inflammatory signals) platelets can change their surface expression and release their granule content thereby engaging different immune cells. Platelets form HAGs and initiate innate immune responses in the presence of TLR agonists and viruses such as EMCV, CVB, dengue, flu, HIV. Platelets can interact with DC through their P-selectin, activate them to become Ag-presenting through their CD154. By releasing α- or δ-granule content which leads to IgG (IgG1, IgG2, IgG3) production and control of T-cell function, platelets engage the adaptive immune response. Similarly, platelets are able to activate the endothelium, make it more permeable and mediate leukocyte trafficking to the inflamed endothelium. Proteins in bold represent changes of expression on the platelet surface. Continuous lines represent direct binding; dotted lines represent interaction through secretion. Abbreviations: HAG-heterotypic aggregates; Ag-antigen; 5-HT-serotonin; PF4-platelet factor 4; CMV- cytomegalovirus; EMCV-encephalomyocarditis virus; CVB-coxsackievirus B;

Figure 3. Platelet and circulating cell interactions during infection initiate the innate or adaptive immune response

Platelets achieve cell-to-cell communication during bacterial or viral infection either by direct interaction with WBCs through surface expression of platelet proteins or through indirect protein release from their α- or δ-granules. EMCV-activated platelets interact with neutrophils in a TLR7-dependent manner. CVB-activated platelets bind to neutrophils in a PS-dependent manner. Dengue and influenza increase microparticle release; dengue-mediated microparticles contain IL-1β. HCMV-activated platelets interact with neutrophils, monocytes, B-cells, T-cells and DCs, suggesting activation of innate and adaptive immune responses. Vaccinia-bound platelets have reduced aggregation potential in the presence of ADP, collagen, or thrombin. The specific pathways by which platelets respond to Herpes simplex virus (HSV)1 or HSV2 are currently unknown. During bacterial infection, platelet interactions with complement C3 opsonized bacteria through GP1b (CD42) lead to slowing of bacterial clearance. DCs recognize the platelet-bacterial complexes, thereby, inducing adaptive immunity. These platelet-bacterial interactions are true for Gram-positive or Gram-negative bacteria. Abbreviations: WBC-white blood cells; 5HT-serotononin; VEGF-vascular endothelial growth factor; PS-phosphatidylserine; C3-complement C3; EMCV-encephalomyocarditis virus; hCMV-human cytomegalovirus; CVB-coxsackievirus B; HIV-human immunodeficiency virus;

Figure 4. Platelet vascular and circulating cellular communication by non-protein-dependent mechanisms

Platelets and platelet-like particles (PLPs) have been shown to communicate with vascular cells in several protein-independent manners, specifically through mitochondrial and RNA transfer. RNA can be transferred from platelets to endothelial cells, monocytes, macrophages, and cancer cells. Inversely, RNA can be taken up by platelets from endothelial cells, monocytes, and cancer cells. Mitochondrial transfer from platelets to neutrophils can also occur. Microparticles mediate a significant number of these communication pathways.