Histones induce rapid and profound thrombocytopenia in mice
Histones induce rapid and profound thrombocytopenia in mice
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DOI：
10.1182/blood-2011-01-332676
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发表时间：
2011-09-29
期刊：
影响因子：
20.3
通讯作者：
Wagner, Denisa D.
中科院分区：
文献类型：
--
作者：
Fuchs, Tobias A.;Bhandari, Ashish A.;Wagner, Denisa D.
组蛋白从垂死的细胞中释放出来，有助于感染期间的抗菌防御。然而，细胞外组蛋白是一把双刃剑，因为它们也会损害宿主组织并可能导致死亡。我们研究了组蛋白与血小板的相互作用。组蛋白与血小板结合，诱导钙内流，并募集血浆粘附蛋白如纤维蛋白原以诱导血小板聚集。因此，纤维蛋白原交联了含有组蛋白的血小板并引发了微聚集。纤维蛋白原与α IIb β 3整合素的相互作用不是这个过程所必需的，但对于大血小板聚集体的形成是必要的。在体内输注与血小板相关的组蛋白，并在给药后数分钟内引起严重的血小板减少症。缺乏血小板或α IIb β 3整联蛋白的小鼠可以免受组蛋白诱导的死亡，但不能免受组蛋白诱导的组织损伤。高浓度肝素可防止组蛋白与血小板相互作用，保护小鼠免受组蛋白诱导的血小板减少症、组织损伤和死亡。肝素和组蛋白是进化维持的。组蛋白可以结合联合收割机杀微生物和促血栓形成特性，以对抗入侵的微生物并在损伤后维持止血。肝素可以提供一种先天的对抗机制来中和组蛋白并减少附带组织损伤。（血。2011; 118（13）：3708-3714）
Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen crosslinked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with alpha IIb beta 3 integrins were not required for this process but were necessary for the formation of large platelet aggregates. Infused histones associated with platelets in vivo and caused a profound thrombocytopenia within minutes after administration. Mice lacking platelets or alpha IIb beta 3 integrins were protected from histone-induced death but not from histone-induced tissue damage. Heparin, at high concentrations, prevented histone interactions with platelets and protected mice from histone-induced thrombocytopenia, tissue damage, and death. Heparin and histones are evolutionary maintained. Histones may combine microbicidal with prothrombotic properties to fight invading microbes and maintain hemostasis after injury. Heparin may provide an innate counter mechanism to neutralize histones and diminish collateral tissue damage. (Blood. 2011; 118(13):3708-3714)