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

IL-6 信号传导对急性炎症（血栓炎症）时肝脏血小板生成素生成、血小板周转和血小板活化的影响

• 批准号: 500397648
• 负责人: Professorin Dr. Margitta Elvers
• 金额: --
• 依托单位: Institut für Biochemie und Molekularbiologie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/500397648?language=en
• 关键词: Impact; IL; signaling; hepatic; thrombopoietin

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.

白介素 6 (IL-6) 是一种急性期细胞因子，参与炎症。在 IL-6 经典信号传导中，IL-6 通过膜结合 IL-6 受体 (IL-6R) 刺激靶细胞，IL-6R 在配体结合后与信号传导受体蛋白 gp130 结合，从而激活 Janus 激酶 (JAK) 和转录因子 (STAT)。仅表达 gp130 的细胞可以对与可溶形式的 IL-6R 结合的 IL-6 做出反应，这一过程被称为反式信号传导。血小板中存在 sIL-6R 和 gp130 已得到不同研究组的证实，IL-6 可能能够通过激活 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 的细胞因子信号传导，并且与心血管事件发生率相关。此外，IL-6 信号传导通过血小板生成素 (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 表达升高并从剩余肝组织中释放，血小板计数迅速恢复。 IL-6R 在这些过程中发挥着至关重要的作用，以确保止血。在新的初步研究中，我们能够提供证据，证明 AMI 后血小板周转增强，肝脏中 Asgr1 和 IL-6r 表达增强，导致 TPO 血浆水平增强。此外，Lgp130-CD4-Cre 小鼠中血小板计数升高表明 gp130 和 CD4+ T 细胞参与血小板数量的控制。此外，我们发现IL-6信号在血小板活化中发挥作用，但IL-6反式信号不足以调节血小板活化。迄今为止，连接 IL-6 信号传导和血小板周转和生成以及血小板活化和血小板介导的炎症的途径和蛋白质在很大程度上尚不清楚。在此，我们假设 IL-6 信号传导是 TPO 稳态、血小板活化和血栓形成及相关炎症（血栓炎症）的主要调节因子。因此，我们希望通过实验来遵循当前提案中的三个主要目标。首先，我们想要详细验证 IL-6 信号传导对肝脏中 TPO 表达和释放的影响。其次，我们想在实验小鼠（AMI 小鼠模型）中研究 IL-6 信号传导在血小板激活和血小板介导的炎症中的作用。第三，我们将分析 AMI 患者的血小板更新，这可能导致血小板活化升高和表面糖基化的变化，特别是作为第一种转化方法的唾液酸损失。