Identification and verification of Hub Biomarkers and Immune-Related Pathways Participating in the Trabecular Meshwork after using Corticosteroid

Abstract

Background The corticosteroids is associated with increased Intraocular pressure (IOP), especially in the way of topical application. However, there is no clear explanation for the cause and possible molecular mechanism. It was reported that immune cells may impact on matrix metalloproteinase pathway and IOP. This study aimed to identify the key biomarkers and immunological pathways involved in corticosteriod-induced changes in trabecular meshwork (TM). Methods The Gene Expression Omnibus database was used to retrieve the expression profile for GSE124114 and GSE37474. Based on differential expression analysis (DEGs), hub markers for the possible molecular pathways in the TM following the use of corticosteroids were mined. The hub gene modules linked to higher IOP were found using weighted gene co-expression network analysis (WGCNA), and the immune cells' presence of the TM was assessed using CIBERSORT. R (version 3.6.1) was used to carry out enrichment analysis on DEGs. Protein-protein interaction (PPI) networks of DEGs were generated by the STRING database. An analysis of receiver operating characteristic curves was conducted with the combined datasets GSE6298 and GSE65240 to verify the expression of hub genes. Results A total of 30 DEGs were recognized. Based on gene ontology (GO) and KEGG pathway analyses, these DEGs were primarily involved in positive regulation of cytokine production and phenylalanine metabolism. Two hub modules were enriched on rheumatoid arthritis pathway and the AGE-RAGE signaling pathway in diabetic complications The PPI network found the two most closely connected hub genes (TSC22D3 and FKBP5) among 24 overlapping hub genes. The most significant link shown by the immune infiltration data was Macrophages M0. TSC22D3 was strongly related with Macrophages M0 (R = 0.75, p = 0.018). ROC curve analysis demonstrated FKBP5 gene was important in TM treated with steroid hormone. FKBP5 gene was verified through the consolidated GSE6298, GSE65240 database. Conclusions Two essential genes (TSC22D3 and FKBP5) contribute to the understanding of the molecular pathways behind corticosteroid-induced ocular hypertension. TSC22D3 was strongly related to macrophages, which was associated with the pathogenesis of TM. FKBP5 may serve as an unique diagnostic marker in plasma samples of individuals with elevated IOP.