Immune Disease Institute, Boston, MA, USA.
Blood. 2011 Sep 29;118(13):3708-14. doi: 10.1182/blood-2011-01-332676. Epub 2011 Jun 23.
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 cross-linked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with αIIbβ3 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 αIIbβ3 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.
组蛋白从死亡的细胞中释放出来，并在感染期间有助于抗菌防御。然而，细胞外组蛋白是一把双刃剑，因为它们也会损伤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，诱导钙离子内流，并募集血浆黏附蛋白（如纤维蛋白原）诱导血小板聚集。由此，纤维蛋白原交联含组蛋白的血小板并引发微聚集。纤维蛋白原与 αIIbβ3 整合素的相互作用对于这个过程不是必需的，但对于形成大的血小板聚集是必需的。在体内输注的组蛋白与血小板结合，并在给药后几分钟内导致严重的血小板减少症。缺乏血小板或 αIIbβ3 整合素的小鼠免受组蛋白诱导的死亡保护，但不能免受组蛋白诱导的组织损伤保护。肝素在高浓度下可防止组蛋白与血小板相互作用，并可防止小鼠发生组蛋白诱导的血小板减少症、组织损伤和死亡。肝素和组蛋白在进化上是被维持的。组蛋白可能将杀菌与促血栓形成特性结合起来，以抵抗入侵的微生物并在受伤后维持止血。肝素可能提供一种先天的拮抗机制来中和组蛋白并减少附带的组织损伤。
