The Immune Nature of Platelets Revisited

Abstract

Platelets are the primary cellular mediators of hemostasis and this function firmly acquaints them with a variety of inflammatory processes. For example, platelets can act as circulating sentinels by expressing Toll-like receptors (TLR) that bind pathogens and this allows platelets to effectively kill them or present them to cells of the immune system. Furthermore, activated platelets secrete and express many pro- and anti-inflammatory molecules that attract and capture circulating leukocytes and direct them to inflamed tissues. In addition, platelets can directly influence adaptive immune responses via secretion of, for example, CD40 and CD40L molecules. Platelets are also the source of most of the microvesicles in the circulation and these miniscule elements further enhance the platelet's ability to communicate with the immune system. More recently, it has been demonstrated that platelets and their parent cells, the megakaryocytes (MK), can also uptake, process and present both foreign and self-antigens to CD8+ T-cells conferring on them the ability to directly alter adaptive immune responses. This review will highlight several of the non-hemostatic attributes of platelets that clearly and rightfully place them as integral players in immune reactions.

Keywords: Antigen processing and presentation; Bacteria; CD40L; Chemokines; Cytokines; Immune response; Microvesicles; Platelets; TLR; Viruses.

Figure 1

Platelets, via several cell surface and internalized receptor molecules, can readily bind to and uptake many different viruses. Platelet receptors for viruses: platelets and viruses can directly interact via a plethora of surface receptors. CMV binds to platelets via TLR2, EMCV interacts via TLR7, rotavirus utilizes GPIa/IIa to bind to platelets and Hantavirus and adenovirus interact with platelets via GPIIb/IIIa. EBV–platelet interaction occurs via CR2. HIV and DV bind to lectin receptors such as CLEC-2 and DC-SIGN. HIV further interacts with CXCR4 and CCL3 and CCL5. Platelets express the Coxsackie virus-specific receptor, CAR, and HCV interacts with platelets via GPVI. CAR, Coxsackie-adenovirus receptor; CLEC-2, C-type lectin domain family 2; CCL, chemokine (C–C motif) ligand; CMV, cytomegalovirus; CR, complement receptor; CXCR4, C–X–C chemokine receptor type 4; EBV, Epstein–Barr virus; EMCV, encephalomyocarditis virus; DC-SIGN, DC-specific intercellular adhesion molecule-3-grapping non-integrin; DV, Dengue virus; FcγRII, Fc receptor γ II; GP, glycoprotein; HCV, hepatitis virus C; HIV, human immunodeficient virus; IgG, immunoglobulin G; TLR, toll-like receptor. Adapted from [210].

Figure 2

Pleiotropic effects by which platelet membrane CD40/CD40L might modulate interactions between immune cells. Platelets can interact with numerous immune cells such as B-cells, T-cells, macrophages, neutrophils, EC, natural killer cells and DC. Communications with these cells can induce a spectrum of immune-related events. Th, T-helper; Treg, regulatory cell; NK, Natural Killer cell; DC, Dendritic cell.

Figure 3

Pleiotropic Platelet membrane receptors by which Platelets can interact with bacteria and numerous immune cells such as B-cells, T-cells, monocytes, neutrophils, epithelium, endothelium and tumor cells. Arrows and brackets show some of the major interactions. CD40, CD40 molecule; CD40L, CD40 ligand (CD154); sCD40L, soluble CD40L; LPS, Lipopolysaccharide; LP, Lipoprotein; dsRNA, Double-stranded RNA; ssRNA, Single-stranded RNA; CAPs, carboxy(alkylpyrrole) protein adducts; PMV, Platelet microvesicule; IL-1β, Interleukin-1 beta; NAP-2, Neutrophil Activating protein-2; EMT, epithelial-mesenchymal transition proteins; CXCL4, Chemokine (C-X-C motif) ligand 4; CXCL7, Chemokine (C-X-C motif) ligand 7; CCL3, Chemokine (C-C motif) ligand 3; CCL5, Chemokine (C-C motif) ligand 5; TGF-β, Transforming growth factor beta; TC-1, Thrombocidin-l ;TC-2, thrombocidin-lI; CLEC-2, C-type lectin domain family 2; DC-SIGN, Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin; TLRs, Toll Like Receptors.