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.
Keywords: c-Jun N-terminal kinase; estradiol; ferroptosis; histones H3; reactive oxygen species; sepsis.
© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.