Extracellular histone H3 facilitates ferroptosis in sepsis through ROS/JNK pathway

• Published in: Immunity, Inflammation and Disease Vol. 11; no. 1; pp. e754 - n/a
• Main Authors: Han, Zhijun, Yuan, Zhizhou, Shu, Linfei, Li, Tao, Yang, Fan, Chen, Lei
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.01.2023; Wiley
• Subjects: Animals; c‐Jun N‐terminal kinase; Disease; Enzymes; estradiol; Estrogens; Ferroptosis; Histones - metabolism; histones H3; Hospitals; Human Umbilical Vein Endothelial Cells; Humans; Infections; Iron; Laboratory animals; Life sciences; Lipopolysaccharides - toxicity; MAP Kinase Signaling System; Mortality; reactive oxygen species; Reactive Oxygen Species - metabolism; Sepsis; c-Jun N-terminal kinase; ferroptosis; sepsis; histones H3; reactive oxygen species; estradiol
• ISSN: 2050-4527; 2050-4527
• DOI: 10.1002/iid3.754

Introduction Previous evidence realized the critical role of histone in disease control. The anti‐inflammatory function of estradiol (E2) in sepsis has been documented. We here intended to unveil the role of extracellular histone H3 in sepsis regarding cell ferroptosis and the role of E2 in a such mechanism. Methods Clinical sample, cecal ligation and puncture (CLP)‐induced animal models and lipopolysaccharides (LPS)‐induced cell models were prepared for testing relative expression of extracellular histone H3 and E2 as well as analyzing the role of extracellular histone H3 and E2 in sepsis concerning cell viability, reactive oxygen species (ROS), and ferroptosis. Results Under sepsis, we found increased ferroptosis and extracellular histone H3 content, but reduced E2 concentration. Extracellular histone H3 facilitated ferroptosis of human umbilical vein endothelial cells (HUVECs) induced by LPS through activating the ROS/c‐Jun N‐terminal kinase (JNK) pathway. Moreover, E2 antagonized the effect of extracellular histone H3 on LPS‐induced HUVEC ferroptosis and sepsis injury in CLP‐induced animal models. Conclusion We highlighted that extracellular histone H3 facilitated lipopolysaccharides‐induced HUVEC ferroptosis via activating ROS/JNK pathway, and such an effect could be antagonized by E2. We highlighted that extracellular histone H3 facilitated lipopolysaccharides‐induced human umbilical vein endothelial cells ferroptosis via activating reactive oxygen species/JNK pathway. Such effect could be antagonized by E2. Key points Sepsis increases ferroptosis and extracellular histone H3 content, but reduces estradiol (E2) concentration. Extracellular histone H3 induces ferroptosis of human umbilical vein endothelial cells (HUVECs) induced by lipopolysaccharides (LPS). E2 antagonizes the effect of extracellular histone H3 on LPS‐induced HUVEC ferroptosis. Extracellular histone H3 promotes the ferroptosis of HUVECs by activating JNK pathway. E2 antagonized the effect of extracellular histone H3 on sepsis injury in animal models.