Abstract
BackgroundSpinal cord injury (SCI) is one of the most devastating diseases with a high incidence rate around the world. SCI-related neuropathic pain (NeP) is a common complication, whereas its pathomechanism is still unclear. The purpose of this study is to identify key genes and cellular components for SCI-related NeP by an integrated transcriptome bioinformatics analysis.MethodsThe gene expression profile of 25 peripheral blood samples from chronic phase SCI patients (E-GEOD-69901) and 337 normal peripheral blood samples were downloaded from ArrayExpress and Genotype-Tissue Expression Portal (GTEx), respectively. A total of 3,368 normal peripheral blood mononuclear cells (PBMC) were download from Sequence Read Archive (SRA713577). Non-parametric tests were used to evaluate the association between all of differential expression genes (DEGs) and SCI-related NeP. CellPhoneDB algorithm was performed to identify the ligand–receptor interactions and their cellular localization among single PBMCs. Transcription factor (TF) enrichment analysis and Gene Set Variation Analysis (GSVA) were used to identify the potential upstream regulatory TFs and downstream signaling pathways, respectively. Co-expression analysis among significantly enriched TFs, key cellular communication genes and differentially expressed signaling pathways were performed to identify key genes and cellular components for SCI-related NeP.ResultsA total of 2,314 genes were identified as DEGs between the experimental and the control group. Five proteins (ADRB2, LGALS9, PECAM1, HAVCR2, LRP1) were identified in the overlap of proteins in the significant ligand-receptor interactions of PBMCs and protein-protein interaction (PPI) network based on the DEGs. Only HAVCR2 was significantly associated with NeP (P = 0.005). Besides, the co-expression analysis revealed that TF YY1 had significantly co-expression pattern with cellular communication receptor HAVCR2 (R = −0.54, P < 0.001) in NK cells while HAVCR2 was also co-expressed with mTOR signaling pathway (R = 0.57, P < 0.001). The results of RT-qPCR and external dataset validation supported the signaling axis with the most significant co-expression patterns.ConclusionIn peripheral blood of chronic SCI, HAVCR2 might act as a key receptor on the surface of NK cells and interact with ligand LGALS9 secreted by CD14+ monocytes, inhibiting NK cells through mTOR signaling pathway and ultimately predicting the occurrence of SCI-related NeP. This hypothetical signaling axis may provide prognostic biomarkers and therapeutic targets for SCI-related NeP.
Highlights
Spinal cord injury (SCI) refers to the damage to the spinal cord due to trauma, disease or degeneration (Cheshire et al, 1996; Brienza et al, 2018)
The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested some critical pathways were significantly associated with cellular communication, such as “Endocytosis,” “Protein processing in endoplasmic reticulum,” “RNA transport,” and “NF-κB signaling pathway” (Figure 2C)
The results suggested that transcription factor (TF) Yin and Yang 1 TF (YY1) (Figure 9A, P < 0.001) and CEBPB (Figure 9C, P < 0.001) were upregulated in the peripheral blood of patients with SCI compared with patients with fractures but no SCI and normal adults
Summary
Spinal cord injury (SCI) refers to the damage to the spinal cord due to trauma, disease or degeneration (Cheshire et al, 1996; Brienza et al, 2018). The global SCI incidence is 40 to 80 new cases per million population per year (New et al, 2014). It induces locomotor deficits or even complete paralysis physically, and generates despairing psychological stress (Budh and Osteraker, 2007). Spinal cord injury (SCI) is one of the most devastating diseases with a high incidence rate around the world. The purpose of this study is to identify key genes and cellular components for SCI-related NeP by an integrated transcriptome bioinformatics analysis
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