Department of Blood Sciences, Royal Liverpool and Broadgreen University Hospitals National Health Service Trust, Liverpool L7 8XP, United Kingdom.
J Immunol. 2013 Sep 1;191(5):2495-502. doi: 10.4049/jimmunol.1203181. Epub 2013 Jul 26.
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.
C-反应蛋白（CRP）是一种急性期蛋白，在先天免疫中对抗细菌感染起着重要的防御作用，但它也在许多非传染性疾病中上调。这种高度保守的分子在从感染、炎症、创伤和恶性肿瘤等疾病中的一般功能尚不清楚。在本文中，我们证明 CRP 可抵御因广泛细胞死亡而释放到循环中的组蛋白的毒性。在体外，CRP 可显著减轻组蛋白诱导的内皮细胞损伤、通透性增加和血小板聚集。在体内，CRP 通过抑制内皮损伤、血管通透性和凝血激活，挽救了接受致死剂量组蛋白挑战的小鼠，这反映在肺水肿、出血和血栓形成的显著减少。在患者中，CRP 水平的升高可显著增加在循环中中和细胞外组蛋白的能力。我们还证实 CRP 可在体外与单个组蛋白相互作用，并在 CRP 和组蛋白水平升高的患者的血清中形成 CRP-组蛋白复合物。CRP 能够与含有磷脂的脂质体竞争与组蛋白的结合。这解释了 CRP 如何防止组蛋白整合到细胞膜中，否则组蛋白会通过钙离子内流作为细胞外组蛋白引起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 CRP 对循环组蛋白的解毒作用将是人类的一种通用宿主防御机制。
