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

白细胞介素-6 （IL-6）是一种急性期细胞因子，参与炎症反应。在IL-6经典信号传导中，IL-6通过与信号受体蛋白gp130结合的膜结合IL-6受体（IL-6R）刺激靶细胞，从而激活Janus激酶（JAKs）和转录因子（STATs）。仅表达gp130的细胞可以对与IL-6R的可溶性形式结合的IL-6产生反应，这一过程被称为反式信号传导。不同的组证实了il - 6r和gp130在血小板中的存在，IL-6可能通过激活JAK2和STAT3来激活血小板并加速血栓形成。在急性心肌梗死（AMI）期间观察到通过IL-6和sIL-6R传递的细胞因子信号，并与心血管事件发生率相关。此外，IL-6信号通过促血小板生成素（TPO）刺激血小板生成来调节血小板生成。最近，我们报道了部分肝切除术（PHx）后，通过激活Ashwell Morell受体(AMR)/IL-6R-JAK2-STAT信号通路，导致TPO表达和释放升高，血小板计数迅速恢复。IL-6R在这些过程中起着重要的止血作用。在新的初步研究中，我们能够提供证据，证明AMI后血小板周转增加，肝脏中Asgr1和IL-6r的表达增加，导致TPO血浆水平增加。此外，在Lgp130-CD4-Cre小鼠中，血小板计数升高表明gp130和CD4+ t细胞参与了血小板数量的控制。此外，我们发现IL-6信号在血小板活化中起作用，但IL-6反式信号不足以调节血小板活化。迄今为止，将IL-6信号与血小板周转和产生以及血小板活化和血小板介导的炎症联系起来的途径和蛋白质在很大程度上是未知的。在这里，我们假设IL-6信号是TPO稳态、血小板激活和血栓相关炎症（血栓-炎症）的主要调节因子。因此，我们希望实验性地遵循当前提案中的三个主要目标。首先，我们想详细验证IL-6信号通路对肝脏TPO表达和释放的影响。其次，我们想研究IL-6信号在实验性小鼠（AMI小鼠模型）血小板活化和血小板介导炎症中的作用。第三，我们将分析AMI患者的血小板周转，这可能导致血小板活化升高和表面糖基化的变化，特别是唾液酸的损失作为第一翻译方法。

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.