Human CRP Defends against the Toxicity of Circulating Histones
Human CRP Defends against the Toxicity of Circulating Histones
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DOI：
10.4049/jimmunol.1203181
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发表时间：
2013-09-01
影响因子：
4.4
通讯作者：
Toh, Cheng-Hock
中科院分区：
文献类型：
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作者：
Abrams, Simon T.;Zhang, Nan;Toh, Cheng-Hock
C-反应蛋白（CRP）是一种急性时相蛋白，在先天免疫中对细菌感染起重要的防御作用，但在许多非感染性疾病中也上调。这种高度保守的分子在感染、炎症、创伤和恶性肿瘤等疾病中的一般功能尚不清楚。在这篇文章中，我们证明了CRP可以保护人体免受广泛细胞死亡后释放到循环中的组蛋白的毒性。在体外，CRP显着加剧组蛋白诱导的内皮细胞损伤，通透性增加，血小板聚集。在体内，CRP通过抑制内皮损伤、血管渗透性和凝血激活来挽救用致死剂量的组蛋白攻击的小鼠，如肺水肿、出血和血栓形成的显著减少所反映的。在患者中，CRP的升高显著增加了中和循环中细胞外组蛋白的能力。我们还证实了CRP在体外与单个组蛋白相互作用，并在CRP和组蛋白均升高的患者血清中形成CRP-组蛋白复合物。CRP能够与含磷脂的脂质体竞争结合组蛋白。这解释了CRP如何阻止组蛋白整合到细胞膜中，否则这将诱导钙内流作为细胞外组蛋白引起的细胞毒性的主要机制。由于组蛋白升高发生在与广泛细胞死亡相关的许多严重疾病的急性期，因此循环组蛋白的CRP解毒将是人类的通用宿主防御机制。
C-reactive protein (CRP) is an acute-phase protein that plays an important defensive role in innate immunity against bacterial infection, but it is also upregulated in many noninfectious diseases. The generic function of this highly conserved molecule in diseases that range from infection, inflammation, trauma, and malignancy is not well understood. In this article, we demonstrate that CRP defends the human body against the toxicity of histones released into the circulation after extensive cell death. In vitro, CRP significantly alleviates histone-induced endothelial cell damage, permeability increase, and platelet aggregation. In vivo, CRP rescues mice challenged with lethal doses of histones by inhibiting endothelial damage, vascular permeability, and coagulation activation, as reflected by significant reductions in lung edema, hemorrhage, and thrombosis. In patients, elevation of CRP significantly increases the capacity to neutralize extracellular histones in the circulation. We have also confirmed that CRP interacts with individual histones in vitro and forms CRP-histone complexes in serum from patients with both elevated CRP and histones. CRP is able to compete with phospholipid-containing liposomes for the binding to histones. This explains how CRP prevents histones from integrating into cell membranes, which would otherwise induce calcium influx as the major mechanism of cytotoxicity caused by extracellular histones. Because histone elevation occurs in the acute phase of numerous critical illnesses associated with extensive cell death, CRP detoxification of circulating histones would be a generic host defense mechanism in humans.