Umprogrammierung von Megakaryozyten und Thrombozyten als Reaktion auf bakterielle Infektionen
Immunologie
Parasitologie und Biologie der Erreger tropischer Infektionskrankheiten
Zellbiologie
Zusammenfassung der Projektergebnisse
Established and emerging evidence indicates that platelets do not only have hemostatic but also immunological functions, such as host defenses against bacterial infections. However, the role of their precursor cells, the megakaryocytes, in the antibacterial immune response is largely unexplored. This project aimed to investigate changes in the gene expression profile of megakaryocytes in response to bacterial infection, and whether an altered genetic code is invested into newly-released platelets. Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and a potent stimulant in bacterial sepsis. Using a murine model of sepsis, we showed that after inducing polymicrobial peritonitis, LPS circulates in the blood and reaches the bone marrow. RNA sequencing analysis of LPS-stimulated human cord blood-derived megakaryocytes revealed upregulation of genes predominantly belonging to the cytokine or chemokine family. We continued to study IL6 as a candidate gene. Compared to healthy controls, this inflammatory cytokine was elevated in a multiplex cytokine analysis of plasma from septic patients with Gram-negative bacteremia. Notably, LPS did not only upregulate IL6 mRNA expression, but also induced IL6 protein secretion in human cord blood-derived megakaryocytes. Further, upregulated IL6 mRNA was transferred from megakaryocytes to developing platelets in mouse and human sepsis. Taken together, the results of this project demonstrate that IL6 is induced and released by megakaryocytes upon LPS stimulation in human and mice using in vitro and in vivo models of sepsis. Further studies are needed to identify involved surface receptors and signaling pathways. In conclusion, megakaryocytes are able to reprogram their gene expression profile in response to LPS challenge which may help to clear bacterial infections. This could include effects mediated by the megakaryocyte secretome in the bone marrow milieu and effects mediated by an altered transcriptome of newly-released platelets manifesting in the blood circulation. The findings of this project could lead to new therapeutic strategies for treating bacterial infections.
Projektbezogene Publikationen (Auswahl)
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Lipopolysaccharide induces a cytokine and chemokine response in megakaryocytes. Gordon Research Conference – Cell Biology of Megakaryocytes and Platelets, 2019, Galveston, Texas, USA
Krauel K, Campbell RA, Middleton EA, Rondina MT, Bhatlekar S, Montenont E, Blair AM, Weyrich AS
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Lipopolysaccharide induces IL6 and upregulates IL8 expression in megakaryocytes. XXVII Congress of the International Society on Thrombosis and Haemostasis, 2019, Melbourne, Australia
Krauel K, Campbell RA, Middleton EA, Rondina MT, Bhatlekar S, Montenont E, Blair AM, Weyrich AS
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Sepsis alters the transcriptional and translational landscape of human and murine platelets. Blood 2019; 134: 911-923
Middleton EA, Rowley JW, Campbell RA, Grissom CK, Brown SM, Beesley SJ, Schwertz H, Kosaka Y, Manne BK, Krauel K, Tolley ND, Eustes AS, Guo L, Paine R 3rd, Harris ES, Zimmerman GA, Weyrich AS, Rondina MT
