Weighted Gene Coexpression Network Analysis Identified IL2/STAT5 Signaling Pathway as an Important Determinant of Peri-Implantitis.

Objective: Peri-implantitis (PI) is one of the main reasons for dental implant failure. Until now, the etiology and pathogenesis of PI remain unclear.

Methods: In this study, we used differentially expressed genes (DEGs) analysis and gene function enrichment analysis to assess the expression profile of peri-implant bone tissue and gingiva in PI public data from the Gene Expression Omnibus (GEO) database. Then, we used gingival tissues from patients with PI and healthy individual to construct gene coexpression networks to reveal the biological functions of the genes in PI using RNA sequencing data. Afterward, key gene modules were selected to reveal the critical biological process or signaling pathway using Hallmark's gene enrichment and expression analysis of the related pathway members in PI.

Results: DEGs were enriched in the formation of cellular responses to external stimuli in bone tissue. Cytokine production, lymphocyte activation, immune response-regulating signaling pathway, and blood vessel development were the top GO biology process or pathways of the DEGs in gingival tissue. Weighted gene coexpression network analysis (WGCNA) of RNA-seq data was used to assess the results of correlation analysis between modules and traits and correlation analysis between modules and functions. kMEpurple, kMEgreen, and kMEred modules were selected as the key gene modules. Signaling pathways and gene expression analysis were performed on selected modules, such as IL2/STAT5 signaling pathway, TNF signaling pathway via NFB, and angiogenesis were enriched in kMEpurple module. Hedgehog signaling pathway, Wnt -catenin signaling pathway, and IL2/STAT5 signaling pathway were enriched in kMEgreen module. Peroxisome, IL2/STAT5 signaling pathway, and epithelial-mesenchymal transformation process were enriched in kMEred module. All the enrichment results of key modules contained IL2/STAT5 signaling pathway. Differential gene and enrichment analysis based on public data showed differences in gene expression patterns and biological process between bone and gingival tissues in PI. This spatial-temporal heterogeneity is reflected in the formation of cellular responses to external stimuli, which was enriched in bone tissue, but cytokine production, lymphocyte activation, immune response regulating signaling pathway, and blood vessel development were enriched in gingival tissue. WGCNA and Hallmark gene sets enrichment analysis of the gingival tissue expression profile and showed that IL2-mediated activation of immune cells could be a critical mechanism in PI. As a new clinical treatment alternative, we suggest that IL2/STAT5 pathway blockers could be helpful in the treatment of PI.