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Gene expression profiles reveal key pathways and genes associated with neuropathic pain in patients with spinal cord injury.

ABSTRACT: Previous gene expression profiling studies of neuropathic pain (NP) following spinal cord injury (SCI) have predominantly been performed in animal models. The present study aimed to investigate gene alterations in patients with spinal cord injury and to further examine the mechanisms underlying NP following SCI. The GSE69901 gene expression profile was downloaded from the public Gene Expression Omnibus database. Samples of peripheral blood mononuclear cells (PBMCs) derived from 12 patients with intractable NP and 13 control patients without pain were analyzed to identify the differentially expressed genes (DEGs), followed by functional enrichment analysis and protein?protein interaction (PPI) network construction. In addition, a transcriptional regulation network was constructed and functional gene clustering was performed. A total of 70 upregulated and 61 downregulated DEGs were identified in the PBMC samples from patients with NP. The upregulated and downregulated genes were significantly involved in different Gene Ontology terms and pathways, including focal adhesion, T cell receptor signaling pathway and mitochondrial function. Glycogen synthase kinase 3 ? (GSK3B) was identified as a hub protein in the PPI network. In addition, ornithine decarboxylase 1 (ODC1) and ornithine aminotransferase (OAT) were regulated by additional transcription factors in the regulation network. GSK3B, OAT and ODC1 were significantly enriched in two functional gene clusters, the function of mitochondrial membrane and DNA binding. Focal adhesion and the T cell receptor signaling pathway may be significantly linked with NP, and GSK3B, OAT and ODC1 may be potential targets for the treatment of NP.

SUBMITTER: He X

PROVIDER: S-EPMC5364823 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Gene expression profiles reveal key pathways and genes associated with neuropathic pain in patients with spinal cord injury.

He Xijing X Fan Liying L Wu Zhongheng Z He Jiaxuan J Cheng Bin B

Molecular medicine reports 20170222 4

Previous gene expression profiling studies of neuropathic pain (NP) following spinal cord injury (SCI) have predominantly been performed in animal models. The present study aimed to investigate gene alterations in patients with spinal cord injury and to further examine the mechanisms underlying NP following SCI. The GSE69901 gene expression profile was downloaded from the public Gene Expression Omnibus database. Samples of peripheral blood mononuclear cells (PBMCs) derived from 12 patients with ...[more]

PMID: 28260076

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Project description:Background:Spinal 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. Methods:The 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. Results:A 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. Conclusion:In 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.

Project description:BackgroundMany studies have recently highlighted the role of photobiomodulation (PBM) in neuropathic pain (NP) relief after spinal cord injury (SCI), suggesting that it may be an effective way to relieve NP after SCI. However, the underlying mechanisms remain unclear. This study aimed to determine the potential mechanisms of PBM in NP relief after SCI.MethodsWe performed systematic observations and investigated the mechanism of PBM intervention in NP in rats after SCI. Using transcriptome sequencing, we screened CXCL10 as a possible target molecule for PBM intervention and validated the results in rat tissues using reverse transcription-polymerase chain reaction and western blotting. Using immunofluorescence co-labeling, astrocytes and microglia were identified as the cells responsible for CXCL10 expression. The involvement of the NF-κB pathway in CXCL10 expression was verified using inhibitor pyrrolidine dithiocarbamate (PDTC) and agonist phorbol-12-myristate-13-acetate (PMA), which were further validated by an in vivo injection experiment.ResultsHere, we demonstrated that PBM therapy led to an improvement in NP relative behaviors post-SCI, inhibited the activation of microglia and astrocytes, and decreased the expression level of CXCL10 in glial cells, which was accompanied by mediation of the NF-κB signaling pathway. Photobiomodulation inhibit the activation of the NF-κB pathway and reduce downstream CXCL10 expression. The NF-κB pathway inhibitor PDTC had the same effect as PBM on improving pain in animals with SCI, and the NF-κB pathway promoter PMA could reverse the beneficial effect of PBM.ConclusionsOur results provide new insights into the mechanisms by which PBM alleviates NP after SCI. We demonstrated that PBM significantly inhibited the activation of microglia and astrocytes and decreased the expression level of CXCL10. These effects appear to be related to the NF-κB signaling pathway. Taken together, our study provides evidence that PBM could be a potentially effective therapy for NP after SCI, CXCL10 and NF-kB signaling pathways might be critical factors in pain relief mediated by PBM after SCI.

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Gene expression profiles reveal key pathways and genes associated with neuropathic pain in patients with spinal cord injury.

Publications

Gene expression profiles reveal key pathways and genes associated with neuropathic pain in patients with spinal cord injury.

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