New insights into roles of IL-7R gene as a diagnostic biomarker for post-stroke depression

Abstract

Background: Post-stroke depression (PSD) is the most prevalent neuropsychiatric complication following a stroke. The inflammatory theory suggests that PSD may be associated with an overactive inflammatory response. However, research findings regarding inflammation-related indicators in PSD remain inconsistent and elusive. This study aimed to screen the diagnostic markers that helps to distinguish between PSD and post-stroke non-depressed (PSND) patients.

Methods: Two GEO datasets, including patients with major depression disease (MDD) and controls (CON, GSE98793), ischemic stroke (IS) and CON (GSE16561), were used to analyzed differentially expressed genes (DEGs) and perform enrichment analysis. Protein-protein interaction (PPI) network and Random Forest analysis were used to screen the candidate hub genes. CIBERSORT was performed to analyze the immune infiltration. We analyzed the proteins that interact with the hub genes using string database, circRNA-miRNA-mRNA ceRNA network of the hub genes using RNAInter, miRWalk, miRDB and Starbase databases, and the drugs that regulate the hub genes by DSigDB database. We further verified the expression of the hub genes using Quantitative Real-Time PCR from the blood of patients and CON.

Results: From the screened 394 DEGs, the DEGs were found primarily related to activation of immune response. PPI network and random forest analysis obtained the hub genes: IL-7R. ROC analysis showed that IL-7R had a good diagnostic and predictive effect on MDD and IS patients. The proportions of macrophages M0 and monocytes in patients were significantly higher than those in CON. We constructed PPI network and ceRNA network that related to IL-7R. The perturbagen signatures and computational drug signatures were found that can target IL-7R. The expression of IL-7R in MDD, PSND and PSD patients was lower than that in CON, and the expression of IL-7R in PSD patients was lower than that in PSND patients.

Conclusion: These findings indicate that IL-7R may serve as a diagnostic marker to distinguish between PSD and PSND patients, and targeting IL-7R as a therapeutic target could potentially improve treatment outcomes for PSD.

Keywords: IL-7R; major depression; neuroinflammation; post-stroke depression; stroke.

Figure 1

Differentially expressed genes (DEGs) screening. (A) The expression of mRNA in GSE98793 and GSE16561; (B) Heatmap, venn, and volcano plot of in GSE98793 and GSE16561; (C) Venn diagram illustrated the number of shared and unique DEGs.

Figure 2

Functional enrichment analysis. (A) KEGG pathway analysis of DEGs; (B) GO functional analysis of DEGs.

Figure 3

Construction of PPI network. (A, B) The visualization of PPI network analysis of DEGs; the analysis of top 10 DEGs with Degree (C), EPC (D), MCC (E) and MNC (F) algorithms. (G) Venn diagram showed the number of shared and unique DEGs of the four algorithms.

Figure 4

Identification of the candidate hub DEGs. (A) The candidate hub DEGs was performed through RF in GSE98793 (A) and GSE16561 (B); (C) Venn diagram illustrated the number of shared and unique DEGs screened from GSE98793 and GSE16561; (D) Venn diagram showed the candidate hub DEGs screened between RF and above four algorithms.

Figure 5

The ROC curve of the candidate hub DEGs in MDD and IS patients. The expression of IL-7R in GSE98793 (A) and GSE16561 (B); ROC analysis of IL-7R between IS (C) or MDD (D) patients and CON. *** p < 0.001.

Figure 6

Relative prediction about IL-7R. (A) Construction of interacting genes with IL-7R; (B) The predicted miRNA that interacted with IL-7R in three databases; (C) The ceRNA networks. IL-7R are colored in red, miRNAs are colored in yellow, and circRNAs are colored in blue.

Figure 7

Immune infiltration analysis between MDD and CON. (A) The heatmap of relative abundance of 22 immune cells; (B) Cello diagram of immune infiltration of 22 immune cells; (C) Boxplot of immune checkpoint; (D) Pearson correlation analysis between immune cells and IL-7R. ns: no significance, * p < 0.05, ** p < 0.01, ***p < 0.001.

Figure 8

Immune infiltration analysis between IS and CON. (A) The heatmap of relative abundance of 22 immune cells; (B) Cello diagram of immune infiltration of 22 immune cells; (C) Boxplot of immune checkpoint; (D) Pearson correlation analysis between immune cells and IL-7R. ns: no significance, * p < 0.05, ** p < 0.01, ***p < 0.001.

Figure 9

Comparison of (A) HAMD-17 scores, (B) NISS scores and (C) IL-7R expression among groups. CON (n=15): Controls, MDD (n=14): Major depressive disease, PSND (n=14): post-stroke non-depressed, PSD (n=15): Post-stroke depression. ***p<0.001, * p<0.05.