Significance of TLR2 signaling during megakaryocyte development: regulatory cross-talk of miR-125b cytokine induction and MAPK pathway during dengue infection

摘要

Objective: Dengue is a viral infection endemic in more than 100 countries as per the WHO reports with approximately 5.2 million patients worldwide that spreads from mosquitoes to humans. Severe form of dengue fever can cause serious bleeding (low platelets) and death. Megakaryocytes are the immune cells responsible for the production of platelets. The molecular drivers behind platelet defects are mostly ambiguous. Here, we attempted to understand the distinct pathogen-elicited toll-like receptors (TLRs) functions in megakaryocyte biology. To understand the TLR induction and the molecular events that are governed in the mammalian system during dengue infection and to study TLR2-mediated cellular signaling-associated mechanisms with respect to their dimerization partners during dengue infection. Methods: In this study, we used the human Megakaryoblastic cells, DAMI, and treated them with TLR agonists (LPS and Zymosan) and Dengue virus (DNV-II). Results and Discussion: TLR2 could play an important role by dimerizing with TLR1, TLR4, and TLR6, which we induced for functional characterization. We observed that megakaryocyte maturation markers CD-41 and CD-61 were elevated. This augmentation under the LPS and Zymosan system along with DNV Infection was further confirmed. Our analysis also suggested that activation of miR-125b and MAPK signaling led to lipid droplet elevation. This led us to analyze TLR-mediated consequences and their impact on megakaryocyte development under diverse pathogen-elicited conditions. Conclusion: Pathogenic challenges associated with toll-like receptor system activation could further our understanding of the platelet biogenesis mechanistic pathways under various pathogenic circumstances.