Citrullinated Histone H3 Mediates Sepsis-Induced Lung Injury Through Activating Caspase-1 Dependent Inflammasome Pathway.
Citrullinated Histone H3 Mediates Sepsis-Induced Lung Injury Through Activating Caspase-1 Dependent Inflammasome Pathway.
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DOI：
10.3389/fimmu.2021.761345
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发表时间：
2021
影响因子：
7.3
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Tian Y;Li P;Wu Z;Deng Q;Pan B;Stringer KA;Alam HB;Standiford TJ;Li Y
脓毒症是由宿主对感染的反应失调引起的危及生命的器官功能障碍，其通常导致急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）。脓毒症诱导的ARDS的一种新兴机制涉及中性粒细胞/巨噬细胞经历细胞死亡，释放核组蛋白以引起加重肺损伤的组织损伤。虽然已发表的研究集中在未修饰的组蛋白上，但关于瓜氨酸化组蛋白H3（CitH 3）在脓毒症和ALI发病机制中的作用知之甚少。在本研究中，我们发现脓毒症诱导的ARDS患者的CitH 3水平升高，并且与脓毒症患者的PaO 2/FiO 2相关。在小鼠中系统施用CitH 3肽引起肺组织中的Caspase-1活化并引起ALI。用单克隆抗体中和CitH 3改善了小鼠脓毒症模型中的存活率并减弱了ALI。此外，我们证明CitH 3通过激活骨髓来源的巨噬细胞和骨髓来源的树突状细胞中的Caspase-1依赖性炎性体诱导ALI。我们的研究表明CitH 3是脓毒症诱导的ALI期间炎症和死亡率的重要介质。
Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection that often results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). An emerging mechanism of sepsis-induced ARDS involves neutrophils/macrophages undergoing cell death, releasing nuclear histones to cause tissue damage that exacerbates pulmonary injury. While published studies focus on unmodified histones, little is known about the role of citrullinated histone H3 (CitH3) in the pathogenesis of sepsis and ALI. In this study, we found that levels of CitH3 were elevated in the patients with sepsis-induced ARDS and correlated to PaO2/FiO2 in septic patients. Systematic administration of CitH3 peptide in mice provoked Caspase-1 activation in the lung tissue and caused ALI. Neutralization of CitH3 with monoclonal antibody improved survival and attenuated ALI in a mouse sepsis model. Furthermore, we demonstrated that CitH3 induces ALI through activating Caspase-1 dependent inflammasome in bone marrow derived macrophages and bone marrow derived dendritic cells. Our study suggests that CitH3 is an important mediator of inflammation and mortality during sepsis-induced ALI.