Appropriation of GPIb from platelet-derived extracellular vesicles supports monocyte recruitment in systemic inflammation
Ferrata Storti Foundation
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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-β1 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-β1-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.
Chimen, M., Evryviadou, A., Box, C.L., Harrison, M.J., Hazeldine, J., Dib, L.H., Kuravi, S.J., Payne, H., Price, J.M., Kavanagh, D. and Iqbal, A.J. (2020) 'Appropriation of GPIbα from platelet-derived extracellular vesicles supports monocyte recruitment in systemic inflammation', Haematologica, 105(5), pp.1248-1261.
Dynodwr Gwrthrych Digidol (DOI)https://doi.org/10.3324/haematol.2018.215145
Article published in Haematologica on 29 August 2019 (online) available open access at: https://doi.org/10.3324/haematol.2018.215145.
Cardiff Metropolitan University (Grant ID: Cardiff Metropolian (Internal))
This work was supported by a British Heart Foundation (BHF) programme grant (RG/12/7/29693 to GER), a BHF Chair (CH/03/003 to SPW), a Royal Society Dorothy Hodgkin research fellowship (DH160044 to MC) and a BHF studentship (FS/14/42/30956, GER). This work was also supported by grants from the NIHR Surgical Reconstruction Microbiology Research Centre (SRMRC) (JL, JH) and the Scar Free foundation (JL, PH). The NIHR-SRMRC is a partnership between University Hospitals Birmingham NHS Foundation Trust, the University of Birmingham and the Royal Centre for Defence Medicine. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. AB is supported by British Heart Foundation Senior Basic Science Research Fellowship (FS/19/30/34173). This work was also supported by a BHF Accelerator Award (AA/18/2/34218).
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