title: Poly (I:C) downregulates platelet production and function through type I interferon.
abstract: Thrombocytopenia is a frequent complication of viral infections; the underlying mechanisms appear to depend on the identity of the virus involved. Previous research, including reports from our group, indicates that as well as having antiviral activity type I interferons (IFN I) selectively downregulate platelet production. In this study we extended understanding of the role of endogenous IFN I in megakaryo/thrombopoiesis by evaluating platelet and megakaryocyte physiology in mice treated with polyinosinic:polycytidylic acid [poly (I:C)], a synthetic analogue of double-stranded RNA, Toll-like receptor-3 ligand and strong IFNβ inducer. Mice-treated with poly (I:C) showed thrombocytopaenia, an increase in mean platelet volume and abnormal haemostatic and inflammatory platelet-mediated functionality, indicated by decreased fibrinogen binding and platelet adhesion, prolonged tail bleeding times and impaired P-Selectin externalisation, RANTES release and thrombin-induced platelet-neutrophil aggregate formation. These changes were associated with an increase in size and an abnormal distribution of bone marrow megakaryocytes within the vascular niche and were directly correlated with the plasmatic and bone marrow IFNβ levels. All these effects were absent in genetically modified mice lacking the IFN I receptor. Our results suggest that IFN I is the central mediator of poly (I:C)-induced thrombocytopenia and platelet dysfunction and indicate that these abnormalities are due to changes in the last stages of megakaryocyte development. These data provide new evidence for the role of IFN I in megakaryocyte distribution in the bone marrow niches and its influence on thrombopoiesis and haemostasis.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Rivadeneyra
authors.forename: Roberto Gabriel
authors.initials: RG
authors.lastname: Pozner
authors.forename: Roberto
authors.initials: R
authors.lastname: Meiss
authors.forename: Carlos
authors.initials: C
authors.lastname: Fondevila
authors.forename: Ricardo Martin
authors.initials: RM
authors.lastname: Gómez
authors.affiliation: Mirta Schattner, Institute of Experimental Medicine, Pacheco de Melo 3081, Buenos Aires 1425, Argentina, Tel.: +5411 48073926, Fax: +5411 48050712, Email: mschattner@hematologia.anm.edu.ar.
authors.forename: Mirta
authors.initials: M
authors.lastname: Schattner
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D018946:Chemokine CCL5 / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism*; D008533:Megakaryocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics; D011070:Poly I-C / Q000008:administration & dosage; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D013921:Thrombocytopenia / Q000276:immunology*; D034061:Thrombopoiesis / Q000187:drug effects / Q000235:genetics
chemical_list: D018946:Chemokine CCL5; C508032:Ifnar1 protein, mouse; D019007:P-Selectin; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D005340:Fibrinogen; D011070:Poly I-C
keywords: Platelets; interferon; poly (I:C); thrombocytopaenia; virus