Mou Yujie, Yang Shuo, Yu Jiayun, Chen Xueping, Zhu Yirui, Wang Chunyang, Wan Xiaojie, Yuan Kelan, Huang Xiaodan, Jin Xiuming
Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, PR China; Zhejiang Provincial Key Lab of Ophthalmology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, PR China.
Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, PR China; Zhejiang Provincial Key Lab of Ophthalmology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, PR China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 3):113525. doi: 10.1016/j.intimp.2024.113525. Epub 2024 Nov 4.
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.
角膜新生血管化（CNV）严重影响角膜透明度并破坏眼内环境的稳态。然而，CNV的潜在机制仍不清楚。在本研究中，我们调查了中性粒细胞胞外陷阱（NETs）在CNV中所起的作用以及组蛋白甲基化如何调节NETs的特性。我们使用碱烧伤诱导的小鼠CNV模型和人原代中性粒细胞来观察NETs在CNV过程中的参与情况及其组蛋白甲基化的变化。进行转录组分析以证明NETs在角膜碱烧伤过程中的参与情况。我们使用组蛋白去甲基化酶抑制剂JIB-04来调节NETs的组蛋白甲基化，并探讨其对CNV形成的相关影响。NETs明显参与角膜碱烧伤，并且在体外可被氢氧化钠刺激。分离的NETs加重CNV并促进血管内皮细胞的迁移、增殖和管腔形成，而破坏NETs在体内和体外均能显著改善血管生成和炎症。机制上，NETs的组蛋白甲基化被碱烧伤抑制，并被JIB-04恢复。此外，我们发现JIB-04通过调节NF-κB/ERK/ROS通路减少CNV和NETs的形成。总之，本研究揭示了组蛋白甲基化在调节NETs形成从而影响血管生成方面的新作用，这为CNV和其他新生血管化相关疾病指明了一个新的治疗靶点。
