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

Abstract

Charge interactions play a critical role in the activation of the innate immune system by damage-and pathogen-associated molecular pattern receptors. The ability of these receptors to recognize a wide spectrum of ligands through a common mechanism is critical in host defense. In this article, we argue that platelet glycoprotein receptors that signal through conserved tyrosine-based motifs function as pattern recognition receptors (PRRs) for charged endogenous and exogenous ligands, including sulfated polysaccharides, charged proteins and nanoparticles. This is exemplified by GPVI, CLEC-2 and PEAR1 which are activated by a wide spectrum of endogenous and exogenous ligands, including diesel exhaust particles, sulfated polysaccharides and charged surfaces. We propose that this mechanism has evolved to drive rapid activation of platelets at sites of injury, but that under some conditions it can drive occlusive thrombosis, for example, when blood comes into contact with infectious agents or toxins. In this Opinion Article, we discuss mechanisms behind charge-mediated platelet activation and opportunities for designing nanoparticles and related agents such as dendrimers as novel antithrombotics.

Role of Tyrosine Kinase Syk in Thrombus Stabilisation at High Shear

“…Glycoprotein VI (GPVI) is a platelet immunoglobulin receptor which is known as a receptor for collagen [ 5 ], but in recent years has also been shown to be a receptor for fibrin and fibrinogen, among other predominantly charged ligands [ 6 ]. In vitro flow studies have shown that GPVI contributes to the stability of newly formed platelet aggregates on collagen at high shear through use of the blocking anti-GPVI Fab ACT017, which has more recently been named glenzocimab [ 4 ].…”

Katacine Is a New Ligand of CLEC-2 that Acts as a Platelet Agonist

“…Recently, Montague et al (2021) have proposed the three platelet ITAM receptors as PRRs as they are activated by a miscellaneous group of polyvalent charged ligands. 14 The charged nature of katacine is consistent with this mechanism. However, we did not observe clear phosphorylation on the FcR gamma chain (∼15 kDa) on whole lysates when treated with katacine, while a marked increase on the phosphorylation was observed when platelets were treated with the GPVI ligand, CRP.…”

“…12,13 The dependency on the four charged residues has led to the hypothesis that CLEC-2 may be a pattern recognition receptor (PRR) on platelets. 14 The identification of small-molecule ligands for CLEC-2 is essential for the development of orally available inhibitors as this is the preferred route of delivery for long-term antithrombotics. To address this objective, we set up a highthroughput screening (HTS) assay using a small-molecule library based on the podoplanin-CLEC-2 interaction.…”

“… 12 13 The dependency on the four charged residues has led to the hypothesis that CLEC-2 may be a pattern recognition receptor (PRR) on platelets. 14 …”

Pro-thrombotic changes associated with exposure to ambient ultrafine particles in patients with chronic obstructive pulmonary disease: roles of lipid peroxidation and systemic inflammation

“…This seems counterintuitive but could be explained by previous animal studies showing that UFP exposure caused thrombotic and inflammatory effects at different lags [ 18 , 51 , 52 ]. However, there is also some evidence that exposure to UFP can increase thrombus formation independent of inflammation [ 53 ], as nanoparticles may penetrate into the blood circulation with the potential for direct effects on platelet activation [ 54 ].…”