Appropriation of GPIbα from platelet-derived extracellular vesicles supports monocyte recruitment in systemic inflammation

Abstract

Interactions between platelets, leukocytes and the vessel wall provide alternative pathological routes of thrombo-inflammatory leukocyte recruitment. We found that when platelets were activated by a range of agonists in whole blood, they shed platelet-derived extracellular vesicles which rapidly and preferentially bound to blood monocytes compared to other leukocytes. Platelet-derived extracellular vesicle binding to monocytes was initiated by P-selectin-dependent adhesion and was stabilised by binding of phosphatidylserine. These interactions resulted in the progressive transfer of the platelet adhesion receptor GPIbα to monocytes. GPIbα +monocytes tethered and rolled on immobilised von Willebrand Factor or were recruited and activated on endothelial cells treated with TGF-b1 to induce the expression of von Willebrand Factor. In both models monocyte adhesion was ablated by a function-blocking antibody against GPIbα. Monocytes could also bind platelet-derived extracellular vesicle in mouse blood in vitro and in vivo. Intratracheal instillations of diesel nanoparticles, to model chronic pulmonary inflammation, induced accumulation of GPIbα on circulating monocytes. In intravital experiments, GPIbα + -monocytes adhered to the microcirculation of the TGF-b1-stimulated cremaster muscle, while in the ApoE -/model of atherosclerosis, GPIbα + -monocytes adhered to the carotid arteries. In trauma patients, monocytes bore platelet markers within 1 hour of injury, the levels of which correlated with severity of trauma and resulted in monocyte clearance from the circulation. Thus, we have defined a novel thrombo-inflammatory pathway in which platelet-derived extracellular vesicles transfer a platelet adhesion receptor to monocytes, allowing their recruitment in large and small blood vessels, and which is likely to be pathogenic.

The multifaceted contribution of platelets in the emergence and aftermath of acute cardiovascular events

“…These EVs have the potential to modulate biologic processes distal from the site of platelet activation [47,48]. So far, platelet-derived EVs have been demonstrated to enhance the recruitment of monocytes and neutrophils to the vessel wall during inflammation [49,50]; deposit chemokines that trigger the recruitment of monocytes [51]; directly promote monocyte differentiation into macrophages [52]; alter macrophage genotype and function [53,54]; induce proliferation and transformation of smooth muscle cells to a pro-inflammatory phenotype [55]; upon infiltrating the bone marrow, modulate the behavior of megakaryocytes to alter thrombopoiesis during inflammation [56]. Although these observations might be explained by the action of proteins and lipids carried by EVs, a number of interesting studies have also pointed towards nucleic acids, notably microRNAs (miR), as molecular effectors.…”

Associations of Platelet Count with Inflammation and Response to Anti-TNF-α Therapy in Patients with Ankylosing Spondylitis

“…The inflammation caused by overactivated platelets can further promote the development of thrombosis, atherosclerosis, and cardiovascular diseases ( Barrett et al, 2019 ; Garshick et al, 2020 ; Schnorbus et al, 2020 ). Platelets exert critical roles in the development of inflammatory diseases such as inflammatory bowel disease (IBD) ( Chimen et al, 2019 ; Petrey et al, 2019 ; Nicolai and Massberg, 2020 ). Some studies have uncovered that platelets have important roles in the development of rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) ( Andrianova et al, 2019 ; Olumuyiwa-Akeredolu et al, 2019 ; Tessandier et al, 2020 ).…”

Extracellular Vesicles from Airway Secretions: New Insights in Lung Diseases

“…EVs have been broadly studied because of their association with pathologies, including inflammatory diseases [ 109 , 110 ] cardiovascular diseases [ 111 , 112 ], metabolic diseases [ 113 , 114 ], cancer [ 115 , 116 ] or LD [ 107 , 117 , 118 ]. They have been linked to pro-inflammatory processes, participating in antigen presentation [ 101 , 103 ] or macrophage activation [ 15 ], as well as to immunomodulatory processes [ 106 ].…”