Histone methylation regulates neutrophil extracellular traps to attenuate corneal neovascularization

Corneal neovascularization (CNV) severely affects corneal transparency and disrupts the homeostasis of the ocular environment. However, the underlying mechanism of CNV remains unclear. In this study, we investigated the role of neutrophil extracellular traps (NETs) played in CNV and how histone methylation regulates the characterization of NETs. We used an alkali-burn-induced mice CNV model and human primary neutrophils to observe the involvement of NETs during CNV and change in its histone methylation. Transcriptomic analysis was performed to demonstrate the involvement of NETs during corneal alkali burn. We used the histone demethylase inhibitor JIB-04 to regulate the histone methylation of NETs and explored the related effects on CNV formation. NETs were obviously involved in corneal alkali burn and could be stimulated by NaOH in vitro. Isolated NETs aggravated CNV and promoted migration, proliferation and tube formation of vascular endothelial cells, while disruption of NETs significantly ameliorated angiogenesis and inflammation in vivo and in vitro. Mechanistically, histone methylation of NETs was inhibited by alkali burn and restored by JIB-04. Furthermore, we discovered that JIB-04 reduced CNV and NETs formation by regulating the NF-κB/ERK/ROS pathway. In conclusion, this study claims a novel role for histone methylation in regulating NETs formation and thereby affecting angiogenesis, which indicates a novel therapeutic target for CNV and other neovascularization-related diseases.