Metrnl inhibits choroidal neovascularization by attenuating the choroidal inflammation via inactivating the UCHL-1/NF-κB signaling pathway

作者全名：Zhang, Lanyue; Li, Youjian; Wu, Zhengyu; Shen, Qiang; Zeng, Chunqin; Liu, Han; Zhang, Xuedong; Yang, Jiaxing; Liu, Qiaoling; Tang, Dianyong; Ou, Kepeng; Fang, Yanhong

作者地址：[Zhang, Lanyue; Shen, Qiang; Zeng, Chunqin; Liu, Han; Fang, Yanhong] Chongqing Univ, Jiangjin Hosp, Dept Ophthalmol, Chongqing, Peoples R China; [Li, Youjian; Wu, Zhengyu; Yang, Jiaxing; Liu, Qiaoling; Tang, Dianyong; Ou, Kepeng] Chongqing Univ Arts & Sci, Int Acad Targeted Therapeut & Innovat IATTI, Coll Pharm, Natl & Local Joint Engn Res Ctr Targeted & Innovat, Chongqing, Peoples R China; [Zhang, Xuedong] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Eye Inst,Chongqing Key Lab Ophthalmol, Chongqing Branch,Municipal Div,Natl Clin Res Ctr O, Chongqing, Peoples R China

通信作者：Fang, YH (通讯作者)，Chongqing Univ, Jiangjin Hosp, Dept Ophthalmol, Chongqing, Peoples R China.; Ou, KP (通讯作者)，Chongqing Univ Arts & Sci, Int Acad Targeted Therapeut & Innovat IATTI, Coll Pharm, Natl & Local Joint Engn Res Ctr Targeted & Innovat, Chongqing, Peoples R China.

来源：FRONTIERS IN IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001220609700001

JCR分区：Q1

影响因子：5.7

年份：2024

卷号：15

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Metrnl; choroidal neovascularization; macrophage; NF-kappa B signaling pathway; UCHL-1

摘要：Objective Choroidal neovascularization (CNV) represents the predominant form of advanced wet Age-related Macular Degeneration (wAMD). Macrophages play a pivotal role in the pathological progression of CNV. Meteorin-like (Metrnl), a novel cytokine known for its anti-inflammatory properties in macrophages, is the focus of our investigation into its mechanism of action and its potential to impede CNV progression.Methods Cell viability was evaluated through CCK-8 and EdU assays following Metrnl treatment. Expression levels of inflammatory cytokines and proteins were assessed using quantitative reverse-transcription polymerase chain reaction(qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot techniques. Protein-protein interactions were identified through protein mass spectrometry and co-immunoprecipitation (Co-IP). Additionally, in vivo and in vitro neovascularization models were employed to evaluate angiogenesis.Results Our results revealed downregulated Metrnl levels in the choroid-sclera complex of CNV mice, the aqueous humor of wAMD patients, and activated macrophages. Metrnl overexpression demonstrated a reduction in pro-inflammatory cytokine production, influenced endothelial cell function, and suppressed angiogenesis in choroid explants and CNV models. Through protein mass spectrometry and Co-IP, we confirmed Metrnl binds to UCHL-1 to modulate the NF-kappa B signaling pathway. This interaction inhibited the transcription and expression of pro-inflammatory cytokines, ultimately suppressing angiogenesis.Conclusion In summary, our findings indicate that Metrnl down-regulates macrophage pro-inflammatory cytokine secretion via the UCHL-1/NF-kappa B signaling pathway. This mechanism alleviates the inflammatory microenvironment and effectively inhibits choroidal neovascularization.

基金机构：Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission10.13039/501100012669

基金资助正文：We thank Jiahui Wu (Shanghai Jiao Tong University, China) for her help in building the CNV mouse model, and we would also like to Home for Researchers editorial team (www.home-for-researchers.com) for language editing service.