Platelets: "multiple choice" effectors in the immune response and their implication in COVID-19 thromboinflammatory process

Abstract

Although platelets are traditionally recognized for their central role in hemostasis, the presence of chemotactic factors, chemokines, adhesion molecules, and costimulatory molecules in their granules and membranes indicates that they may play an immunomodulatory role in the immune response, flanking their capacity to trigger blood coagulation and inflammation. Indeed, platelets play a role not only in the innate immune response, through the expression of Toll-like receptors (TLRs) and release of inflammatory cytokines, but also in the adaptive immune response, through expression of key costimulatory molecules and major histocompatibility complex (MHC) molecules capable to activate T cells. Moreover, platelets release huge amounts of extracellular vesicles capable to interact with multiple immune players. The function of platelets thus extends beyond aggregation and implies a multifaceted interplay between hemostasis, inflammation, and the immune response, leading to the amplification of the body's defense processes on one hand, but also potentially degenerating into life-threatening pathological processes on the other. This narrative review summarizes the current knowledge and the most recent updates on platelet immune functions and interactions with infectious agents, with a particular focus on their involvement in COVID-19, whose pathogenesis involves a dysregulation of hemostatic and immune processes in which platelets may be determinant causative agents.

Keywords: COVID-19; immune response modulator; infection; platelet-derived extracellular vesicles; thromboinflammation.

FIGURE 1

Schematic representation of platelet functions in the hemostatic process and during inflammation. Platelet activation induces an increase in the expression on the plasma membrane of the active form of integrin αIIbβ3, followed by platelet aggregation promoting thrombin generation. Platelet‐derived microparticles also favoring the coagulation process. Different types of biological mediators released by α and δ granules lead to pro‐thrombotic and proinflammatory events. The interaction between P‐selectin and leukocytes induces the release of proteases, production of ROS, and expression of TF. CD40L expression supports the recruitment of platelets to the endothelium of blood vessels, which in turn activates endothelial cells and vWF release. An increase in cytokine secretion by neutrophils and monocytes induces platelet activation, which favors inflammatory cytokine production by the platelets themselves. Abbreviations: MO, Monocyte; NE, neutrophil elastase; NETs, neutrophil extracellular traps; NEUT, Neutrophil; PLT, platelet; PS, phosphatidylserine; ROS, reactive oxygen species; TF, tissue factor; TXA2, Thromboxane A2; vWF, von Willebrand factor

FIGURE 2

Schematic representation of platelet functions in innate and adaptive immune responses. Platelets exert a role in both the innate and the adaptive immune response, through the expression of several immune receptors. Key factors for leukocyte recruitment are the expression of Toll‐like receptors (TLRs) and P‐selectin (CD62P), and the release of platelet factor 4 (PF4), CD40L, RANTES, and TGF‐α. A) Activated platelets interact with monocytes and neutrophils to form heterotypic aggregates. These interactions induce secretion of active molecules, including cytokines and chemokines, such as IL‐6, IL‐8, Mac‐1, and TF, modulating inflammation and thrombosis. B) Platelets can adhere to lymphocytes to form platelet‐lymphocyte complexes, with different effects. They affect the CD4+ Th cell response, inducing cytokine production typical of Th‐1, Th‐17, and T‐reg cells. They favor Ig production in B cells and enhance the antiviral cytotoxic responses on CD8+ Th cells. Abbreviations: Ig, Immunoglobulin; Mac‐1, macrophage‐1 antigen; PF4, platelet factor 4; TF, tissue factor; TGF‐α, transforming growth factor‐alpha; Th, T helper; T‐reg, regulatory T cells

FIGURE 3

Schematic representation of platelets and SARS‐CoV‐2 interaction leading to thrombocytopenia, neutrophilia, and lymphopenia. A) Thrombocytopenia is ascribable to platelet consumption, which originates from the vasculopathy induced by the cytokine storm, triggered by the viral infection. Increased expression of CD40 in damaged endothelium induces platelet activation, which favors endothelial inflammation. Platelet consumption is heightened by the impaired ability of pulmonary capillaries to retain megakaryocytes and favor platelet release; bone marrow viral infection also contributes to platelet reduction. Immune thrombosis plays a central role in thrombocytopenia; activation of platelets promotes the formation of immuno‐thrombi, which act as focal points for microbial elimination, concentrating leukocytes and lytic enzymes. B) Neutrophilia is mainly due to platelet activation by pro‐inflammatory cytokines induced by SARS‐CoV‐2 infection, and adhesion molecules expressed by damaged endothelium, which sets off a mutual interaction with neutrophils, enhancing their degranulation and DNA release to form NETs, favoring the coagulation cascade. C) Lymphopenia includes a marked reduction of CD4+ T helper, CD8+ T cytotoxic cells, and NK cells. It is mainly ascribable to cytolytic effects exerted by SARS‐CoV‐2 on infected lymphocytes, or to hyperinflammation induced by the infection, which increases lymphocyte apoptosis through Fas triggered by FasL expressed on activated platelets