Han Yu,1,* Lvyin Luo,2,3,* Rui Zhang,1,* Fabao Xu,1 Xueying Yang,1 Yuhan Wu,1 Dechang Han,1 Xuanzhe Chu,1 Jianqiao Li1 

1Department of Ophthalmology, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 2Department 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; 3Shandong Key Laboratory of Brain Function Remodeling, Jinan, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jianqiao Li, Ophthalmology, Qilu Hospital, Shandong University, No. 107, Wenhua West Road, Jinan, Shandong, 250012, People’s Republic of China, Email jqli@email.sdu.edu.cn

Purpose: 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.
Methods: 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.
Results: 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.
Conclusion: 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.

Keywords: proliferative diabetic retinopathy, inflammatory, bioinformatics analysis, microglia, DR mouse model