Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps
Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps
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DOI：
10.1111/jth.12710
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发表时间：
2014-12-01
影响因子：
10.4
通讯作者：
Manfredi, A. A.
中科院分区：
文献类型：
--
作者：
Maugeri, N.;Campana, L.;Manfredi, A. A.
背景越来越多的证据表明血小板和中性粒细胞参与外周和冠状动脉血栓的形成、稳定和生长。中性粒细胞胞外陷阱（NET）发挥着关键作用。血小板和中性粒细胞之间失调的早期事件的特征尚不清楚。目的在分子水平上确定血小板在无菌条件下诱导 NET 生成的机制。患者/方法通过免疫组织化学和免疫荧光以及血浆中评估的 NET 标记物来确定来自急性心肌梗死患者的 26 个血栓中是否存在 NET。研究了静态和生理流动条件下的体外NET生成。结果冠状动脉血栓主要由活化的血小板、中性粒细胞和紧邻血小板的NET组成。活化的血小板使中性粒细胞产生 NET。当高迁移率族蛋白 1 (HMGB1) 蛋白的竞争性拮抗剂存在时，该事件会减弱。 Hmgb1(-/-)血小板无法引发NET，而HMGB1单独使中性粒细胞产生NET。根据药理学和遗传工具的评估，HMGB1 受体（高级糖基化终产物受体 (RAGE) 的受体）的完整性是 NET 形成所必需的。暴露于 HMGB1 可以防止线粒体电位耗竭，诱导自噬体形成，并延长中性粒细胞的存活时间。这些代谢效应是由自噬的激活引起的。阻断自噬流可恢复血小板 HMGB1 引发的 NET 生成。结论激活的血小板将 HMGB1 呈递给中性粒细胞，并使它们参与自噬和 NET 生成。这一系列事件可能是某些类型的血栓炎症病变的原因，并为分子干预指明了新的途径。
BackgroundIncreasing evidence implicates both platelets and neutrophils in the formation, stabilization, and growth of peripheral and coronary thrombi. Neutrophil extracellular traps (NETs) play a key role. The early events in the deregulated cross-talk between platelets and neutrophils are poorly characterized.ObjectivesTo identify at the molecular level the mechanism through which platelets induce the generation of NETs in sterile conditions.Patients/MethodsThe presence of NETs was determined in 26 thrombi from patients with acute myocardial infarction by immunohistochemistry and immunofluorescence and markers of NETs assessed in the plasma. In vitro NET generation was studied in static and in physiological flow conditions.ResultsCoronary thrombi mainly consist of activated platelets, neutrophils, and NETs in close proximity of platelets. Activated platelets commit neutrophils to NET generation. The event abates in the presence of competitive antagonists of the high mobility group box 1 (HMGB1) protein. Hmgb1(-/-) platelets fail to elicit NETs, whereas the HMGB1 alone commits neutrophils to NET generation. Integrity of the HMGB1 receptor, Receptor for Advanced Glycation End products (RAGE), is required for NET formation, as assessed using pharmacologic and genetic tools. Exposure to HMGB1 prevents depletion of mitochondrial potential, induces autophagosome formation, and prolongs neutrophil survival. These metabolic effects are caused by the activation of autophagy. Blockade of the autophagic flux reverts platelet HMGB1-elicited NET generation.ConclusionsActivated platelets present HMGB1 to neutrophils and commit them to autophagy and NET generation. This chain of events may be responsible for some types of thromboinflammatory lesions and indicates novel paths for molecular intervention.