Regulation of megakaryo/thrombopoiesis by endosomal Toll-like receptors 7 and 8 activation of CD34+ cells in a viral infection model

RODRÍGUEZ, CAMILA SOFÍA; CHARÓ NANCY LORENA; TATTI, SILVIO; GÓMEZ, RICARDO MARTÍN; D'ATRI LINA PAOLA* COMPARTE ÚLTIMA AUTORÍA CON MS; SCHATTNER, MIRTA*

Research and Practice in Thrombosis and Haemostasis

Elsevier

Año: 2023

2475-0379

BackgroundCD34+ cells, megakaryocytes (MKs) and platelets express Toll-like receptors (TLRs) that enable these cells to amplify the host innate immune response. However, the role of TLR7/TLR8 activation in megakaryopoiesis has not yet been investigated.ObjectiveWe evaluated the effect of Coxsackievirus B3 (CVB3) and synthetic TLR7/TLR8 agonists on the development of human MKs and platelet production.MethodsCD34+ cells from human umbilical cord were inoculated with CVB3 or stimulated with synthetic TLR7/TLR8 agonists and then cultured in the presence of thrombopoietin.ResultsCD34+ cells, MKs progenitor cells and mature MKs expressed TLR7 and TLR8 and exposure to CVB3 resulted in productive infection, as determined by the presence of viral infectious particles in culture supernatants. Cell expansion, differentiation into MKs, MK maturation and platelet biogenesis were significantly reduced in CD34+-infected cultures. The reduction in MK growth was not due to an alteration in cell proliferation but was accompanied by an increase in cell apoptosis and pyroptosis. Impairment of MK generation and the maturation of viable cells was also associated with the decreased expression of transcription factors involved in these processes. These effects were completely abrogated by TLR7 but not TLR8 antagonists and mimicked by TLR7 but not TLR8 agonists. CVB3 infection of CD34+ cells increased the immunophenotype of MKs characterized as CD148+/CD48+ or CD41+/CD53+ cells.ConclusionsThese data suggest a novel role for TLR7 in megakaryo/thrombopoiesis that may contribute to a better understanding of the molecular basis underlying thrombocytopenia and the immunological role of MKs in viral infection processes.