Yu Han, Luo Lvyin, Zhang Rui, Xu Fabao, Yang Xueying, Wu Yuhan, Han Dechang, Chu Xuanzhe, Li Jianqiao
Department of Ophthalmology, Qilu Hospital, Shandong University, Jinan, People's Republic of China.
Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, People's Republic of China.
J Inflamm Res. 2025 May 13;18:6229-6243. doi: 10.2147/JIR.S519725. eCollection 2025.
Diabetic retinopathy (DR), one of the most common severe complications of diabetes, has become a leading cause of blindness among the working population without a fundamental treatment. Proliferative DR (PDR) is the advanced stage of DR. Recent studies have shown that inflammation is closely related to PDR, as it promotes leukocyte adhesion, breakdown of the blood-retinal barrier, and pathological neovascularization, but the key regulatory genes involved remained unclear. We aim to identify inflammation-related biomarkers in PDR.
We downloaded and merged PDR-related datasets GSE102485, GSE94019, and GSE60436, comprising a total of 13 control samples and 37 samples from PDR patients, and conducted a joint analysis of inflammation-related genes (IRGs). Differential analysis, functional enrichment analysis, WGCNA and LASSO were used to identify key genes and their functions in the pathogenesis of PDR. Dataset GSE241239, which contains retinal sequencing data from mice, was used for external validation. Additionally, single-cell RNA analysis using GSE165784, which includes five human-derived PDR samples, was conducted to investigate the cellular expression of Fc Gamma Receptor IA (FCGR1A) and Integrin Subunit Alpha L (ITGAL). Finally, the expression of FCGR1A and ITGAL was validated in DR mouse models and high glucose-induced cell models.
Nine key genes associated with the pathogenesis of PDR were identified. Further screening identified FCGR1A and ITGAL as potential therapeutic targets, with single-cell analysis showing their primary distribution in microglia. In vivo and in vitro experiments confirmed localization of FCGR1A and ITGAL in microglia and significant elevation within DR mouse models.
Comprehensive analysis indicates, for the first time, that FCGR1A and ITGAL are key inflammation-related genes involved in the pathogenesis of PDR mediated by microglia. FCGR1A and ITGAL are promising therapeutic targets for PDR.
糖尿病视网膜病变（DR）是糖尿病最常见的严重并发症之一，已成为劳动人口失明的主要原因，且尚无根本治疗方法。增殖性糖尿病视网膜病变（PDR）是DR的晚期阶段。最近的研究表明，炎症与PDR密切相关，因为它促进白细胞黏附、血视网膜屏障破坏和病理性新生血管形成，但其中涉及的关键调控基因仍不清楚。我们旨在鉴定PDR中与炎症相关的生物标志物。
我们下载并合并了与PDR相关的数据集GSE102485、GSE94019和GSE60436，共包括13个对照样本和37个PDR患者样本，并对与炎症相关的基因（IRGs）进行了联合分析。采用差异分析、功能富集分析、加权基因共表达网络分析（WGCNA）和套索回归（LASSO）来鉴定PDR发病机制中的关键基因及其功能。包含小鼠视网膜测序数据的数据集GSE241239用于外部验证。此外，使用包含5个人源PDR样本的GSE165784进行单细胞RNA分析，以研究Fcγ受体IA（FCGR1A）和整合素αL亚基（ITGAL）的细胞表达。最后，在DR小鼠模型和高糖诱导的细胞模型中验证了FCGR1A和ITGAL的表达。
鉴定出9个与PDR发病机制相关的关键基因。进一步筛选确定FCGR1A和ITGAL为潜在治疗靶点，单细胞分析显示它们主要分布在小胶质细胞中。体内和体外实验证实了FCGR1A和ITGAL在小胶质细胞中的定位以及在DR小鼠模型中的显著升高。
综合分析首次表明，FCGR1A和ITGAL是由小胶质细胞介导的PDR发病机制中关键的炎症相关基因。FCGR1A和ITGAL是有前景的PDR治疗靶点。
