Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation
Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation
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DOI：
10.1182/blood-2014-05-573543
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发表时间：
2014-10-02
期刊：
影响因子：
20.3
通讯作者：
Boilard, Eric
中科院分区：
文献类型：
--
作者：
Boudreau, Luc H.;Duchez, Anne-Claire;Boilard, Eric
线粒体 DNA (mtDNA) 是一种高度有效的炎症触发因素，据报道在各种病理情况下的血液细胞外都发现了线粒体 DNA。血液中含有丰富的血小板，可促进止血。尽管缺乏细胞核，血小板仍含有功能性线粒体。激活后，血小板产生称为微粒的细胞外囊泡。我们假设活化的血小板也可以释放线粒体。我们发现，活化的血小板释放有呼吸能力的线粒体，无论是在膜包裹的微粒内还是作为游离的细胞器。细胞外线粒体存在于用于输血的血小板浓缩物中，并且在引起输血患者急性反应（发热非溶血反应、皮肤表现和心血管事件）的血小板浓缩物中存在较高水平。我们确定线粒体是分泌型磷脂酶 A(2) IIA (sPLA(2)-IIA) 的内源性底物，这种磷脂酶对细菌具有特异性，可能反映了线粒体的祖先变形菌起源。 sPLA(2)-IIA 水解线粒体膜会产生促进白细胞活化的炎症介质（即溶血磷脂、脂肪酸和 mtDNA）。活体输血动物的双光子显微镜显示，细胞外线粒体与体内中性粒细胞相互作用，引发中性粒细胞粘附到内皮壁。我们的研究结果发现，由血小板产生的细胞外线粒体处于导致炎症反应的有效机制的中点。
Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside the cells in blood in various pathologies. Platelets are abundant in blood where they promote hemostasis. Although lacking a nucleus, platelets contain functional mitochondria. On activation, platelets produce extracellular vesicles known as microparticles. We hypothesized that activated platelets could also release their mitochondria. We show that activated platelets release respiratory-competent mitochondria, both within membrane-encapsulated microparticles and as free organelles. Extracellular mitochondria are found in platelet concentrates used for transfusion and are present at higher levels in those that induced acute reactions (febrile nonhemolytic reactions, skin manifestations, and cardiovascular events) in transfused patients. We establish that the mitochondrion is an endogenous substrate of secreted phospholipase A(2) IIA (sPLA(2)-IIA), a phospholipase otherwise specific for bacteria, likely reflecting the ancestral proteobacteria origin of mitochondria. The hydrolysis of the mitochondrialmembrane by sPLA(2)-IIA yields inflammatory mediators (ie, lysophospholipids, fatty acids, and mtDNA) that promote leukocyte activation. Two-photon microscopy in live transfused animals revealed that extracellular mitochondria interact with neutrophils in vivo, triggering neutrophil adhesion to the endothelial wall. Our findings identify extracellular mitochondria, produced by platelets, at the midpoint of a potent mechanism leading to inflammatory responses.