Xiangya Hospital, Central South University, Changsha, China.
Department of Surgery, University of Michigan, Ann Arbor, MI, United States.
Front Immunol. 2020 Jan 9;10:2957. doi: 10.3389/fimmu.2019.02957. eCollection 2019.
Sepsis results in millions of deaths every year, with acute lung injury (ALI) being one of the leading causes of mortality in septic patients. As neutrophil extracellular traps (NETs) are abundant in sepsis, neutralizing components of NETs may be a useful strategy to improve outcomes of sepsis. Citrullinated histone H3 (CitH3) has been recently shown to be involved in the NET formation. In this study, we demonstrate that CitH3 damages human umbilical vein endothelial cells (HUVECs) and potentiates NET formation through a positive feedback mechanism. We developed a novel CitH3 monoclonal antibody to target peptidylarginine deiminase (PAD) 2 and PAD 4 generated CitH3. In a mouse model of lethal lipopolysaccharide (LPS) induced shock, neutralizing CitH3 with the newly developed anti-CitH3 monoclonal antibody attenuates inflammatory responses, ameliorates ALI, and improves survival. Our study suggests that effectively blocking circulating CitH3 might be a potential therapeutic method for the treatment of endotoxemia.
脓毒症每年导致数百万人死亡，其中急性肺损伤 (ALI) 是脓毒症患者死亡的主要原因之一。由于中性粒细胞胞外诱捕网 (NETs) 在脓毒症中大量存在，中和 NETs 的成分可能是改善脓毒症预后的一种有效策略。瓜氨酸化组蛋白 H3 (CitH3) 最近被证明参与 NET 的形成。在这项研究中，我们证明 CitH3 通过正反馈机制损伤人脐静脉内皮细胞 (HUVEC) 并增强 NET 的形成。我们开发了一种新型的 CitH3 单克隆抗体来靶向肽基精氨酸脱亚氨酶 (PAD) 2 和 PAD 4 产生的 CitH3。在致死性脂多糖 (LPS) 诱导的休克小鼠模型中，用新开发的抗 CitH3 单克隆抗体中和 CitH3 可减轻炎症反应，改善 ALI 并提高存活率。我们的研究表明，有效阻断循环中的 CitH3 可能是治疗内毒素血症的一种潜在治疗方法。
