Innate immune receptors in platelets and platelet-leukocyte interactions

Abstract

Platelets are chief cells in hemostasis. Apart from their hemostatic roles, platelets are major inflammatory effector cells that can influence both innate and adaptive immune responses. Activated platelets have thromboinflammatory functions linking hemostatic and immune responses in several physiological and pathological conditions. Among many ways in which platelets exert these functions, platelet expression of pattern recognition receptors (PRRs), including TLR, Nod-like receptor, and C-type lectin receptor families, plays major roles in sensing and responding to pathogen-associated or damage-associated molecular patterns (PAMPs and DAMPs, respectively). In this review, an increasing body of evidence is compiled showing the participation of platelet innate immune receptors, including PRRs, in infectious diseases, sterile inflammation, and cancer. How platelet recognition of endogenous DAMPs participates in sterile inflammatory diseases and thrombosis is discussed. In addition, platelet recognition of both PAMPs and DAMPs initiates platelet-mediated inflammation and vascular thrombosis in infectious diseases, including viral, bacterial, and parasite infections. The study also focuses on the involvement of innate immune receptors in platelet activation during cancer, and their contribution to tumor microenvironment development and metastasis. Finally, how innate immune receptors participate in platelet communication with leukocytes, modulating leukocyte-mediated inflammation and immune functions, is highlighted. These cell communication processes, including platelet-induced release of neutrophil extracellular traps, platelet Ag presentation to T-cells and platelet modulation of monocyte cytokine secretion are discussed in the context of infectious and sterile diseases of major concern in human health, including cardiovascular diseases, dengue, HIV infection, sepsis, and cancer.

Platelet Activation and Plasma Levels of Furin Are Associated With Prognosis of Patients With Coronary Artery Disease and COVID-19

“… 2 During pathogen infections, platelets release a variety of potent cytokines or chemokines 72 , 73 and interact with leukocytes as well as endothelial cells and propagate vascular and tissue inflammation. 8 , 74 It is well known that virus infections are associated with thrombocytopenia, platelet hyper-reactivity, and formation of platelet/leukocyte co-aggregates leading to enhanced sequestration within the microcirculation. 75 In critically affected patients, nonsurvivors showed a trend towards a drop in platelet count and leukocytosis.…”

“… 3 Virus-induced respiratory tract infection like an acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with platelet activation and characteristic coagulopathy resulting in thrombotic complications including deep vein thrombosis and pulmonary embolism. 4 – 6 In the case of RNA virus infections such as influenza, platelet activation and formation of platelet/leukocyte co-aggregates may occur early in the course of disease progression 7 , 8 followed by enhanced activation of coagulation and thrombin generation. 9 Enhanced platelet activation and formation of circulating platelet/leukocyte co-aggregates was additionally observed in SARS-CoV-2 infected patients 10 which is associated with a worse clinical outcome of patients with coronavirus disease 2019 (COVID-19).…”

Dengue virus-activated platelets modulate monocyte immunometabolic response through lipid droplet biogenesis and cytokine signaling

“…A limited number of studies have demonstrated that platelets activated by different stimuli signal LD biogenesis in monocytes, providing a new mechanism by which platelets potentiate inflammatory or infectious diseases 23,27 . DENV are recognized by and triggers signaling through multiple pathways in platelets including DC‐sign, TLRs, and CLEC2 26,57–60 . Here, we found that DENV‐ or thrombin‐activated platelets modulate monocyte responses in vitro, with increased secretion of inflammatory mediators (such as CXCL8/IL‐8, IL‐10, and IL‐6), COX‐2 expression, and LD biogenesis.…”

Platelet activation by charged ligands and nanoparticles: platelet glycoprotein receptors as pattern recognition receptors

“…Platelets express many PRRs belonging to multiple families including toll-like receptors (TLRs), NOD-like receptors (NLRs) and C-type lectin-like receptors and are involved in promoting immune responses both in infection and with sterile inflammation. 100 Platelet PRRs recognize a wide range of DAMPs including extracellular/mitochondrial DNA, histones and high mobility group box protein (HMGB)-1. [101][102][103][104] However, most of these receptors are expressed in low level and, for many, platelets lack their downstream signaling components (see below).…”

“…Platelets express several TLRs, including surface TLR-1, -2, -4 and -6, 105,106 with TLR-3, -7 and -9 being located in platelet endosomes and translocated to the surface after activation. 100 TLRs signal via recruitment of Toll/Il-1 receptor (TIR) domain containing adaptors, such as MyD88, TIRAP and TRIF (depending on TLR function), resulting in activation of transcription factors NF-kB, IRFs and MAPKs, increasing pro-inflammatory cytokine production. 107 However, platelet lack many of the TLR signaling proteins and lack a nucleus.…”