Periodic Reporting for period 3 - IMMUNOTHROMBOSIS (Cross-talk between platelets and immunity - implications for host homeostasis and defense)
Okres sprawozdawczy: 2022-09-01 do 2024-02-29
Therefore, my project IMMUNOTHROMBOSIS seeks to investigate interplay between thrombus formation and immune function. Specifically, this project investigates the underlying molecular mechanisms, as well as its role in models of thrombotic as well as inflammatory diseases. I have previously identified a novel effector function of immune responsive platelets – the ability to migrate autonomously. Moreover, I identified an immune cell-mediated feedback loop modulating platelet production. We seek to deepen our understanding of these two key processes to elucidate crucial signaling axes of immunothrombosis ultimately highlight novel treatment options.
In addition, I discovered the interactions between megakaryocytes and immune cells as a previously unknown regulatory mechanism of platelet production. First, I was able to demonstrate that physical interactions of neutrophils with proplatelet protrusions are key to efficient platelet release (thrombopoiesis). Second, I identified plasmacytoid dendritic cells (pDCs) as crucial bone marrow niche cells that regulate the proliferation of megakaryocyte progenitors. When pDCs encounter mature megakaryocytes that undergo thrombopoiesis they release INF-alpha which in turn drives the proliferation of megakaryocyte progenitors (megakaryopoiesis). This fine-tuned coordination between thrombopoiesis and megakaryopoiesis is crucial for megakaryocyte and platelet homeostasis.
I was also able to show an important contribution of IMMUNOTHROMBOSIS to the pathology of severe COVID-19. In cooperation with multiple partners at the hospital we collected and analysed blood and tissue samples of patients with COVID-19 pneumonia. We were able to show that platelets become activated in severe disease and interact with neutrophils. This interaction leads to neutrophil activation which release so called neutrophil extracellular traps (NETs). NETs then form clots in the smaller blood vessels of patients. Interestingly, this is not limited to the lung, but also occurs in the liver, kidney and heart of individuals with severe disease.