Expression and functionality of Toll-like receptor 3 in the megakaryocytic lineage.

Autor: D'Atri LP; Laboratory of Experimental Thrombosis, Institute of Experimental Medicine, CONICET-National Academy of Medicine, Buenos Aires, Argentina., Etulain J, Rivadeneyra L, Lapponi MJ, Centurion M, Cheng K, Yin H, Schattner M
Jazyk: angličtina
Zdroj: Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2015 May; Vol. 13 (5), pp. 839-50. Date of Electronic Publication: 2015 Feb 20.
DOI: 10.1111/jth.12842
Abstrakt: Background: In addition to their key role in hemostasis, platelets and megakaryocytes regulate immune and inflammatory responses, in part through their expression of Toll-like receptors (TLRs). Among the TLRs, TLR3 recognizes dsRNA associated with viral infection. Thrombocytopenia is a frequent complication of viral infection. However, the expression and functionality of TLR3 in megakaryocytes and platelets is not yet well understood.
Objective: To study the expression and functionality of TLR3 in the megakaryocytic lineage.
Methods and Results: RT-PCR, flow cytometric and immunofluorescence assays showed that TLR3 is expressed in CD34(+) cells, megakaryocytes, and platelets. Immunoblotting assays showed that stimulation of megakaryocytes with two synthetic agonists of TLR3, Poly(I:C) and Poly(A:U), activated the nuclear factor-κB (NF-κB), phosphoinositide 3-kinase (PI3K)/Akt, extracellular signal-related kinase (ERK)1/2 and p38 pathways. TLR3-megakaryocyte activation resulted in reduced platelet production in vitro and interferon-β release through the PI3K-Akt and NF-κB signaling pathways. TLR3 ligands potentiated the aggregation mediated by classic platelet agonists. This effect was also observed for ATP release, but not for P-selectin or CD40L membrane exposure, indicating that TLR3 activation was not involved in α-granule release. In addition, TLR3 agonists induced activation of the NF-κB, PI3K-Akt and ERK1/2 pathways in platelets. Reductions in platelet production and platelet fibrinogen binding mediated by Poly(I:C) or Poly(A:U) were prevented by the presence of an inhibitor of the TLR3-dsRNA complex.
Conclusions: Our findings indicate that functional TLR3 is expressed in CD34(+) cells, megakaryocytes, and platelets, and suggest a potential role for this receptor in the megakaryopoiesis/thrombopoiesis alterations that occur in viral infections.
(© 2015 International Society on Thrombosis and Haemostasis.)
Databáze: MEDLINE
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