Impact of IL-6 signaling on hepatic thrombopoietin production, platelet turnover and platelet activation upon acute inflammation (thrombo-inflammation)

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Interleukin-6 (IL-6) is an acute phase cytokine and involved in inflammation. In IL-6 classical signaling, target cells are stimulated by IL-6 via the membrane bound IL-6 receptor (IL-6R) that associates with the signaling receptor protein gp130 upon ligand binding leading to the activation of Janus kinases (JAKs) and the activation of transcription factors (STATs). Cells that only express gp130 can respond to IL-6 bound to the soluble form of the IL-6R, a process that has been termed trans-signaling. The presence of sIL-6R and gp130 in platelets was confirmed by different groups and IL-6 might be able to activate platelets and to accelerate thrombus formation via activation of JAK2 and STAT3. Cytokine signaling via IL-6 and sIL-6R is observed during acute myocardial infarction (AMI) and associated with cardiovascular event rates. Furthermore, IL-6 signaling modulates platelet production by stimulating thrombopoiesis through thrombopoietin (TPO). Recently, we reported that platelet counts were rapidly restored after partial hepatectomy (PHx) via activation of the Ashwell Morell receptor (AMR)/IL-6R-JAK2-STAT signaling pathway leading to elevated TPO expression and release from the remaining liver tissue. The IL-6R plays a crucial role in these processes to ensure hemostasis. In new preliminary studies, we were able to provide evidence for an enhanced platelet turnover after AMI with enhanced expression of Asgr1 and IL-6r in the liver resulting in enhanced TPO plasma levels. Furthermore, elevated platelet counts in Lgp130-CD4-Cre mice suggest that gp130 and CD4+ T-cells are involved in the control of platelet numbers. Besides, we found that IL-6 signaling plays a role in platelet activation but that IL-6 trans-signaling is not sufficient to modulate platelet activation. To date, the pathways and proteins that link IL-6 signaling and platelet turnover and production as well as platelet activation and platelet-mediated inflammation are largely unknown. Here, we hypothesize that IL-6 signaling is a major regulator of TPO homeostasis, platelet activation and thrombosis with associated inflammation (thrombo-inflammation). Therefore, we want to experimentally follow three major objectives in the current proposal. First, we want to validate the impact of IL-6 signaling on TPO expression and release in liver in detail. Second, we want to investigate the role of IL-6 signaling in platelet activation and platelet mediated inflammation in experimental mice (mouse model of AMI). Third, we will analyze the platelet turnover in patients with AMI that might lead to elevated platelet activation and to changes in surface glycosylation, specifically loss of sialic acid as a first translational approach.