Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients With Essential Thrombocythemia.

Autor:	Marín Oyarzún CP; Institute of Medical Research A. Lanari, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.; Department of Hematology Research, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Buenos Aires, Argentina., Glembotsky AC; Institute of Medical Research A. Lanari, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.; Department of Hematology Research, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Buenos Aires, Argentina., Goette NP; Institute of Medical Research A. Lanari, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina., Lev PR; Institute of Medical Research A. Lanari, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.; Department of Hematology Research, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Buenos Aires, Argentina., De Luca G; Institute of Medical Research A. Lanari, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.; Department of Hematology Research, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Buenos Aires, Argentina., Baroni Pietto MC; Institute of Medical Research A. Lanari, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.; Department of Hematology Research, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Buenos Aires, Argentina., Moiraghi B; Department of Hematology, Hospital General de Agudos José María Ramos Mejía, Buenos Aires, Argentina., Castro Ríos MA; Consultorios Hematológicos, Buenos Aires, Argentina., Vicente A; Department of Hematology, Hospital Alemán, Buenos Aires, Argentina., Marta RF; Institute of Medical Research A. Lanari, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.; Department of Hematology Research, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Buenos Aires, Argentina., Schattner M; Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX)- CONICET, National Academy of Medicine, Buenos Aires, Argentina., Heller PG; Institute of Medical Research A. Lanari, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.; Department of Hematology Research, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Buenos Aires, Argentina.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2020 Apr 30; Vol. 11, pp. 705. Date of Electronic Publication: 2020 Apr 30 (Print Publication: 2020).
DOI:	10.3389/fimmu.2020.00705
Abstrakt:	Essential thrombocythemia (ET) is comprised among chronic myeloproliferative neoplasms (MPN) and is caused by driver mutations in JAK 2, CALR , and MPL , which lead to megakaryocyte proliferation and prominent thrombocytosis. Thrombosis remains the main cause of morbidity in ET and is driven by the interplay between blood cells, the endothelium, the clotting cascade, and host-derived inflammatory mediators. Platelet activation plays a key role in the thrombotic predisposition, although the underlying mechanisms remain poorly defined. In addition to their role in hemostasis, platelets participate in innate immunity and inflammation owing to the expression of toll-like receptors (TLR), which recognize inflammatory signals, triggering platelet functional responses. Considering the impact of inflammation on ET procoagulant state, we assessed the contribution of TLR2 and TLR4 to platelet hemostatic and inflammatory properties in ET patients, by using Pam3CSK4 and lipopolysaccharide (LPS) as specific TLR2 and TLR4 ligands, respectively. TLR2 ligation induced increased surface translocation of α-granule-derived P-selectin and CD40L, which mediate platelet interaction with leukocytes and endothelial cells, respectively, and higher levels of dense granule-derived CD63 in patients, whereas PAC-1 binding was not increased and LPS had no effect on these platelet responses. Platelet-neutrophil aggregate formation was elevated in ET at baseline and after stimulation of both TLR2 and TLR4. In addition, ET patients displayed higher TLR2- and TLR4-triggered platelet secretion of the chemokine RANTES (CCL5), whereas von Willebrand factor release was not enhanced, revealing a differential releasate pattern for α-granule-stored inflammatory molecules. TLR-mediated hyperresponsiveness contrasted with impaired or preserved responses to classic platelet hemostatic agonists, such as TRAP-6 and thrombin. TLR2 and TLR4 expression on the platelet surface was normal, whereas phosphorylation of downstream effector ERK1/2 was higher in patients at baseline and after incubation with Pam3CSK4, which may partly explain the enhanced TLR2 response. In conclusion, exacerbated response to TLR stimulation may promote platelet activation in ET, boosting platelet/leukocyte/endothelial interactions and secretion of inflammatory mediators, overall reinforcing the thromboinflammatory state. These findings highlight the role of platelets as inflammatory sentinels in MPN prothrombotic scenario and provide additional evidence for the close intertwining between thrombosis and inflammation in this setting. (Copyright © 2020 Marín Oyarzún, Glembotsky, Goette, Lev, De Luca, Baroni Pietto, Moiraghi, Castro Ríos, Vicente, Marta, Schattner and Heller.)
Databáze:	MEDLINE
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