Poly (I:C) downregulates platelet production and function through type I interferon

Leonardo Rivadeneyra; Roberto Gabriel Pozner; Roberto Meiss; Carlos Fondevila; Ricardo Martin Gómez; Mirta Schattner

doi:10.1160/TH14-11-0951

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2015; 114(05): 982-993
DOI: 10.1160/TH14-11-0951

Cellular Haemostasis and Platelets

Schattauer GmbH

Poly (I:C) downregulates platelet production and function through type I interferon

Leonardo Rivadeneyra

¹Laboratory of Experimental Thrombosis, Institute of Experimental Medicine-CONICET, National Academy of Medicine, Buenos Aires, Argentina

,

Roberto Gabriel Pozner

¹Laboratory of Experimental Thrombosis, Institute of Experimental Medicine-CONICET, National Academy of Medicine, Buenos Aires, Argentina

,

Roberto Meiss

²Department of Pathology, Institute of Oncological Research, National Academy of Medicine, Buenos Aires, Argentina

,

Carlos Fondevila

³Bazterrica Clinic, Buenos Aires, Argentina

,

Ricardo Martin Gómez

⁴Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina

,

Mirta Schattner

¹Laboratory of Experimental Thrombosis, Institute of Experimental Medicine-CONICET, National Academy of Medicine, Buenos Aires, Argentina

› Institutsangaben

Abstract

Summary

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 IFNp 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 IFNp 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.

Keywords

Platelets - poly (I:C) - thrombocytopaenia - virus - interferon

Volltext

Referenzen

References
1 Flaujac C, Boukour S, Cramer-Borde E. Platelets and viruses: an ambivalent relationship. Cell Mol Life Sci 2010; 67: 545-556.
2 Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004; 5: 987-995.
3 Theofilopoulos AN, Baccala R, Beutler B. et al. Type I interferons ([alpha]/[beta]) in immunity and autoimmunity. Annu Rev Immunol 2005; 23: 307-336.
4 Le Bon A, Tough DF. Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 2002; 14: 432-436.
5 Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol 2014; 14: 36-49.
6 Novick D, Cohen B, Rubinstein M. The human interferon alpha/beta receptor: characterization and molecular cloning. Cell 1994; 77: 391-400.
7 Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011; 34: 637-650.
8 Iannacone M, Sitia G, Isogawa M. et al. Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc Natl Acad Sci USA 2008; 105: 629-634.
9 Alexopoulou L, Holt AC, Medzhitov R. et al. Recognition of double-stranded RNA and activation of NF-[kappa]B by Toll-like receptor 3. Nature 2001; 413: 732-738.
10 Pozner RG, Ure AE, Jaquenod de Giusti C. et al. Junin virus infection of human hematopoietic progenitors impairs in vitro proplatelet formation and platelet release via a bystander effect involving type I IFN signaling. PLoS Pathog 2010; 6: e1000847.
11 Wang Q, Miyakawa Y, Fox N. et al. Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1. Blood 2000; 96: 2093-2099.
12 Yamane A, Nakamura T, Suzuki H. et al. Interferon-alpha 2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes. Blood 2008; 112: 542-550.
13 Negrotto S, De Giusti CJ, Lapponi MJ. et al. Expression and functionality of type I interferon receptor in the megakaryocyte lineage. J Thromb Haemost 2011; 9: 2477-2485.
14 Wang BX, Rahbar R, Fish EN. Interferon: current status and future prospects in cancer therapy. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Res 2011; 31: 545-552.
15 Aranda F, Vacchelli E, Obrist F. et al. Trial Watch: Toll-like receptor agonists in oncological indications. Oncoimmunol 2014; 3: e29179.
16 Martins KA, Bavari S, Salazar AM. Vaccine adjuvant uses of poly-IC and derivatives. Expert Rev Vacc 2015; 14: 447-459.
17 Malaver E, Romaniuk MA, D'Atri LP. et al. NF-kappaB inhibitors impair platelet activation responses. J Thromb Haemost 2009; 7: 1333-1343.
18 Rivadeneyra L, Carestia A, Etulain J. et al. Regulation of platelet responses triggered by Toll-like receptor 2 and 4 ligands is another non-genomic role of nuclear factor-kappaB. Thromb Res 2014; 133: 235-243.
19 Christopher MJ, Liu F, Hilton MJ. et al. Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization. Blood 2009; 114: 1331-1339.
20 Rondina MT, Garraud O. Emerging evidence for platelets as immune and inflammatory effector cells. Front Immunol 2014; 5: 653.
21 Tucker K, Sage T, Gibbins J. Clot Retraction. In: Platelets and Megakaryocytes. Springer; New York: 2012. pp. 101-107.
22 Chu SG, Becker RC, Berger PB. et al. Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J Thromb Haemost 2010; 8: 148-156.
23 Bath PM, Butterworth RJ. Platelet size: measurement, physiology and vascular disease. Blood Coagul Fibrinol 1996; 7: 157-161.
24 Noris P, Klersy C, Zecca M. et al. Platelet size distinguishes between inherited macrothrombocytopenias and immune thrombocytopenia. J Thromb Haemost 2009; 7: 2131-2136.
25 Schmitt A, Guichard J, Masse JM. et al. Of mice and men: comparison of the ultrastructure of megakaryocytes and platelets. Exp Hematol 2001; 29: 1295-1302.
26 Harker LA, Marzec UM, Kelly AB. et al. Prevention of thrombocytopenia and neutropenia in a nonhuman primate model of marrow suppressive chemotherapy by combining pegylated recombinant human megakaryocyte growth and development factor and recombinant human granulocyte colony-stimulating factor. Blood 1997; 89: 155-165.
27 Sola-Visner MC, Christensen RD, Hutson AD. et al. Megakaryocyte size and concentration in the bone marrow of thrombocytopenic and nonthrombocytopenic neonates. Pediatr Res 2007; 61: 479-484.
28 Avecilla ST, Hattori K, Heissig B. et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med 2004; 10: 64-71.
29 Niswander LM, Fegan KH, Kingsley PD. et al. SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury. Blood 2014; 124: 277-286.
30 Zimmer S, Steinmetz M, Asdonk T. et al. Activation of endothelial toll-like receptor 3 impairs endothelial function. Circulation Res 2011; 108: 1358-1366.
31 D'Atri LP, Etulain J, Rivadeneyra L. et al. Expression and functionality of Toll-like receptor 3 in the megakaryocytic lineage. J Thromb Haemost. 2015 Epub ahead of print.
32 Reimer T, Brcic M, Schweizer M. et al. poly(I:C) and LPS induce distinct IRF3 and NF-kappaB signaling during type-I IFN and TNF responses in human macrophages. J Leukocyte Biol 2008; 83: 1249-1257.
33 Ernstoff MS, Kirkwood JM. Changes in the bone marrow of cancer patients treated with recombinant interferon alpha-2. Am J Med 1984; 76: 593-596.
34 Kreft A, Nolde C, Busche G. et al. Polycythaemia vera: bone marrow histopathology under treatment with interferon, hydroxyurea and busulphan. Eur J Haematol 2000; 64: 32-41.
35 Sata M, Yano Y, Yoshiyama Y. et al. Mechanisms of thrombocytopenia induced by interferon therapy for chronic hepatitis B. J Gastroenterol 1997; 32: 206-210.