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Influence of the platelet-derived DAMP HMGB1 on thrombosis and inflammation

血小板源性 DAMP HMGB1 对血栓形成和炎症的影响

基本信息

批准号：
269589288
负责人：
Professor Dr. Meinrad Paul Gawaz, since 2/2017
金额：
--
依托单位：
Innere Medizin III: Kardiologie und Kreislauferkrankungen
依托单位国家：
德国
项目类别：
Clinical Research Units
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/269589288?language=en
关键词：
Influence platelet derived DAMP HMGB1

项目摘要

High-mobility group box 1 (HMGB1) is a "damage associated molecular pattern" molecule (DAMP), which plays a central role in tissue damage and sterile inflammation. Platelets also express and, upon platelet activation, release HMGB1, thereby potentially affecting tissue repair and regeneration as well as immunological processes. The influence of platelet-derived HMGB1 on such cellular functions is poorly understood. We have previously shown that platelets inhibit recruitment of mesenchymal stem cells (MSC) to apoptotic cardiac myocytes and fibroblasts through HMGB1/toll-like receptor (TLR)-4 interaction, which may have implications on the outcome of myocardial damage (Vogel et al., JBC, 2014). Apoptotic, but not necrotic cell death, constitutes a key stimulus for the recruitment of MSC to damaged tissue and tumor cells - a tropism that is mediated via hepatocyte groth factor (HGF) (Vogel et al., BBRC, 2010; Vogel et al., CMLS, 2013) and regulated by platelet-derived HMGB1 through down-regulation of HGF receptor MET (Vogel et al., JBC, 2014). Further, platelets induce migration and survival of monocytes by binding of HMGB1 to RAGE (receptor of advanced glycation end products) and TLR-4 (unpublished). In monocyte-platelet aggregates, HMGB1-driven anti-apoptotic effects could be detected, as well. Moreover, we have identified an HMGB1-induced prothrombotic and proaggregatory effect for platelets, which was mediated via cGKI, a cGMP-dependent protein kinase. The purpose of this project is to investigate the role of HMGB1 for platelet function as well as identify HMGB1-mediated interactions of platelets with monocytes. In addition to cell biolocical approaches, we will perform ex vivo and in vivo studies with RAGE, TLR-4, MyD88, and cGKI knockout mice. The specific contribution of platelet-derived HMGB1 will be assessed by using recently generated mice with a platelet-specific HMGB1 defect (PF4-Cre; HMGB1-flox/flox). In models such as Fe(III)-chlorideinduced thrombosis or intestinal ischemia, infiltrating monocytes and platelets will be detected with intravital microscopy in the respective regions by using CX3CR1-eGFP/+ reporter mice or ROSA-mT/mG mice. In in vivo models of ischemic stroke and myocardial infarction, the relevance of plateletderived HMGB1 for these diseases will finally be determined. In prospective patient cohorts, we will measure platelet surface expression and release of HMGB1 and evaluate its role for coronary heart disease and stroke, in order to define patient subgroups that show a particularly high response to new therapeutic approaches.

高迁移率组框1 （HMGB1）是一种“损伤相关分子模式”分子（DAMP），在组织损伤和无菌炎症中起核心作用。血小板也表达HMGB1，并在血小板激活后释放HMGB1，从而潜在地影响组织修复和再生以及免疫过程。血小板来源的HMGB1对这些细胞功能的影响尚不清楚。我们之前的研究表明，血小板通过HMGB1/toll样受体(TLR)-4相互作用抑制间充质干细胞（MSC）向凋亡的心肌细胞和成纤维细胞募集，这可能对心肌损伤的结果有影响（Vogel等人，JBC, 2014）。细胞凋亡，而非坏死细胞死亡，是MSC向受损组织和肿瘤细胞募集的关键刺激因素——这一趋向性是通过肝细胞生长因子（HGF）介导的（Vogel等人，BBRC, 2010； Vogel等人，CMLS, 2013），并通过下调HGF受体MET受血小板源性HMGB1调控（Vogel等人，JBC, 2014）。此外，血小板通过HMGB1与RAGE（晚期糖基化终产物受体）和TLR-4的结合诱导单核细胞的迁移和存活（未发表）。在单核细胞-血小板聚集体中，也可以检测到hmgb1驱动的抗凋亡作用。此外，我们还发现了hmgb1诱导的血小板的血栓形成和促聚集作用，这是通过cGKI（一种cgmp依赖性蛋白激酶）介导的。本项目的目的是研究HMGB1在血小板功能中的作用，以及确定HMGB1介导的血小板与单核细胞的相互作用。除了细胞生物学方法外，我们还将对RAGE、TLR-4、MyD88和cGKI敲除小鼠进行体内和体外研究。通过使用新近生成的具有血小板特异性HMGB1缺陷（PF4-Cre; HMGB1-flox/flox）的小鼠来评估血小板来源的HMGB1的特异性贡献。在Fe(III)-氯化物诱导的血栓形成或肠缺血等模型中，使用CX3CR1-eGFP/+报告小鼠或ROSA-mT/mG小鼠，通过活体显微镜在各自区域检测浸润的单核细胞和血小板。在缺血性卒中和心肌梗死的体内模型中，血小板来源的HMGB1与这些疾病的相关性将最终确定。在前瞻性患者队列中，我们将测量血小板表面HMGB1的表达和释放，并评估其在冠心病和中风中的作用，以确定对新治疗方法表现出特别高反应的患者亚组。