PLXNB2 Regulates Monocyte-Mediated Inflammation and Intercellular Communication in the Pathogenesis of Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is a severe microvascular complication of diabetes, with a complex pathogenesis in which inflammatory responses and abnormal intercellular communication play pivotal roles. As crucial immune cells, monocytes play a central role in the inflammatory processes of DR by secreting various signaling molecules and interacting with other retinal cells, thereby jointly driving disease progression. However, the key molecules that regulate monocyte function and intercellular communication in DR remain incompletely elucidated. This study aims to investigate the role of PLXNB2 in the pathogenesis of DR, particularly its regulatory effects on monocyte-mediated inflammation and intercellular communication. The novelty of this study lies in the integration of WGCNA, differential expression analysis, machine learning, SHAP interpretation, single-cell transcriptomics, and cell-cell communication analysis to systematically identify PLXNB2 as a potential regulator of monocyte-associated inflammation in DR. This study employed bioinformatics approaches to systematically identify candidate genes associated with DR. WGCNA was leveraged to construct gene co-expression networks using DR and NDR samples, and differential gene expression analysis was performed to identify gene modules and key genes associated with DR. Subsequently, functional enrichment analysis was conducted on the relevant genes. Machine learning, in conjunction with SHAP value analysis, was employed to accurately screen for key genes driving the DR phenotype. To further investigate cellular mechanisms, single-cell transcriptomic and cell-cell communication analyses were performed, focusing on monocyte characteristics and intercellular signaling in DR patient samples. Ultimately, this study identified and focused on PLXNB2 as a candidate molecule potentially involved in monocyte-mediated inflammation and pathological intercellular communication in DR. After comprehensive gene screening using WGCNA, machine learning, and single-cell transcriptomics, PLXNB2 was found to be the most important gene. PLXNB2 showed strong diagnostic relevance for distinguishing DR from NDR samples and was identified by SHAP analysis as a major contributor to the model prediction. It was discovered that its expression level was closely related to the improvement of Diabetic Retinopathy (DR). Single-cell analysis showed that PLXNB2 significantly altered the molecular landscape of monocytes, and there were clear enhancements in the expression patterns of their genes. Single-cell transcription may have an association with Diabetic Retinopathy (DR), but it does not demonstrate that PLXNB2 causes transcriptional remodeling. Our findings indicate that PLXNB2 can serve as a diagnostic biomarker and a potential therapeutic target for DR. Mechanistically, PLXNB2 may regulate monocyte communication via the ANXA1-FPR1 ligand-receptor pair, mediating anti-inflammatory pathways to inhibit inflammation and cell migration, and participating in apoptotic clearance as well as immune cell chemotaxis and activation, thereby providing mechanistic evidence for PLXNB2 as a therapeutic target for DR. This integrative multi-omics analysis identifies PLXNB2 as a promising monocyte- associated biomarker linked to inflammatory regulation and altered intercellular communication in diabetic retinopathy.