Platelet-derived exosomes promote neutrophil extracellular trap formation during septic shock
Platelet-derived exosomes promote neutrophil extracellular trap formation during septic shock
复制标题
血小板衍生的外泌体促进败血性休克期间中性粒细胞胞外陷阱的形成
DOI：
10.1186/s13054-020-03082-3
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发表时间：
2020-06-29
期刊：
影响因子：
15.1
通讯作者：
Shi, Xueyin
中科院分区：
文献类型：
--
作者：
Jiao, Yang;Li, Weiwei;Shi, Xueyin
背景图已被证明是败血症期间中性粒细胞外陷阱（净）形成的有效活化剂。但是，与人血小板介导的净产生有关的介质和分子途径的定义仍然很差。循环血浆主要来自血小板的循环血浆外泌体可能会在败血症期间诱导血管凋亡和心肌功能障碍。但是，它们在净形成中的作用尚不清楚。这项研究旨在检测血小板来源的外泌体是否可以在败血性休克期间促进净形成并确定所涉及的潜在机制。将与健康对照患者的血浆或与人类血小板的超级泡沫相结合，将外源性核中性嗜中性粒细胞（PMN）与外泌体共培养。脂多糖（LPS）。使用致命的盲肠结扎和穿刺（CLP）小鼠模型在体内模仿败血症。然后，检测到净形成和分子途径。反应性分量（DSDNA和MPO-DNA复合物）在用败血性休克患者衍生的外泌体治疗中显着增加，并与疾病的严重程度和结果呈正相关。在动物CLP模型中，血小板耗竭降低了血浆外泌体浓度，净形成和肺损伤。机械研究表明，外泌体高运动组蛋白1（HMGB1）和/或miR-15b-5p和miR-378a-3p通过AKT/MTOR自噬途径诱导净形成。此外，结果表明，IκB激酶（IKK）控制败血性休克中的血小板衍生的外泌体分泌。ConclusionsPlatelet衍生的外泌体在败血症和随后的器官损伤中促进过多的净形成。这一发现表明，血小板衍生的外泌体在败血症中的作用不明，并可能导致新的治疗方法。
BackgroundPlatelets have been demonstrated to be potent activators of neutrophil extracellular trap (NET) formation during sepsis. However, the mediators and molecular pathways involved in human platelet-mediated NET generation remain poorly defined. Circulating plasma exosomes mostly originating from platelets may induce vascular apoptosis and myocardial dysfunction during sepsis; however, their role in NET formation remains unclear. This study aimed to detect whether platelet-derived exosomes could promote NET formation during septic shock and determine the potential mechanisms involved.MethodsPolymorphonuclear neutrophils (PMNs) were cocultured with exosomes isolated from the plasma of healthy controls and septic shock patients or the supernatant of human platelets stimulated ex vivo with phosphate buffer saline (PBS) or lipopolysaccharide (LPS). A lethal cecal ligation and puncture (CLP) mouse model was used to mimic sepsis in vivo; then, NET formation and molecular pathways were detected.ResultsNET components (dsDNA and MPO-DNA complexes) were significantly increased in response to treatment with septic shock patient-derived exosomes and correlated positively with disease severity and outcome. In the animal CLP model, platelet depletion reduced plasma exosome concentration, NET formation, and lung injury. Mechanistic studies demonstrated that exosomal high-mobility group protein 1 (HMGB1) and/or miR-15b-5p and miR-378a-3p induced NET formation through the Akt/mTOR autophagy pathway. Furthermore, the results suggested that IκB kinase (IKK) controls platelet-derived exosome secretion in septic shock.ConclusionsPlatelet-derived exosomes promote excessive NET formation in sepsis and subsequent organ injury. This finding suggests a previously unidentified role of platelet-derived exosomes in sepsis and may lead to new therapeutic approaches.