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Increased expression of hub gene CXCL10 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterized by overactive inflammation and aberrant activation of lymphocytes. Chemokine C-X-C motif ligand 10 (CXCL10) has an important role in the initiation and deterioration of SLE. However, the expression levels of CXCL10 mRNA in T-helper (Th) cells and B lymphocytes from SLE patients have remained elusive. In the present study, a Bioinformatics analysis of differentially expressed gene (DEG) profiles obtained from RNA sequencing data for three matched samples was performed to explore the hub genes, mainly through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction analysis. Furthermore, the expression of CXCL10 in peripheral blood mononuclear cells (PBMCs), CD4+ Th cells and CD19+ B cells of 108 subjects, including 66 SLE patients and 42 healthy controls, was confirmed by reverse transcription-quantitative PCR. In addition, 4 single-nucleotide polymorphism (SNP) loci in the 3'-untranslated region of CXCL10 were assessed using the Snapshot SNP genotyping assay. A total of 152 clustered DEGs mainly accumulated in immune-associated GO terms and interferon-associated pathways were identified. The expression of CXCL10, one of the central genes in the interaction network cluster (the degree of interaction, MCODE score=28.414), was 6.27-fold higher in SLE patients compared with control patients. Furthermore, CXCL10 mRNA was confirmed to be elevated in PBMCs and CD19+ B cells of patients with SLE (P<0.001 for the two cell types). However, no significant difference in CD4+ T lymphocytes was present (P=0.881). In addition, no polymorphism was identified in four selected loci from the samples. Taken together, the present results demonstrated that CXCL10, one of the hub genes in the pathogenesis of SLE, is upregulated in PBMCs and B lymphocytes of patients with SLE, although none of the SNPs selected for analysis in the present study were identified to have any potential associations with SLE.

SUBMITTER: Zhang R

PROVIDER: S-EPMC6781829 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Increased expression of hub gene CXCL10 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus.

Zhang Ruixian R Li Ya Y Pan Bangpin B Li Yi Y Liu Aimin A Li Xiaolan X

Experimental and therapeutic medicine 20190917 5

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterized by overactive inflammation and aberrant activation of lymphocytes. Chemokine C-X-C motif ligand 10 (CXCL10) has an important role in the initiation and deterioration of SLE. However, the expression levels of CXCL10 mRNA in T-helper (Th) cells and B lymphocytes from SLE patients have remained elusive. In the present study, a Bioinformatics analysis of differentially expressed gene (DEG) profiles obtained from R ...[more]

PMID: 31616519

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Project description:BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease with a complicated pathogenesis, and its aetiology has not been clearly unveiled. The lack of effective diagnosis and treatment methods makes it necessary to explore the molecular mechanism of SLE. We aimed to identify some critical signalling pathways and key competing endogenous RNAs (ceRNAs) underlying the molecular mechanism of SLE and to map out the systematic signalling networks by integrating the data on different kinds of RNAs.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from both SLE patients and healthy subjects, RNA was extracted from the PBMCs, and RNA libraries including ribosomal RNA-depleted strand-specific libraries and small RNA libraries were built for deep RNA sequencing (RNA-seq). RNA-seq yielded differential expression profiles of lncRNAs/circRNAs/miRNAs/mRNAs related to SLE. The DAVID database (v. 6.8) was employed for Gene Ontology (GO) and KEGG pathway analysis. ceRNA networks (circRNA/lncRNA-miRNA-mRNA) were constructed and visualized using Cytoscape software (v. 3.5.0). The TargetScan and miRanda databases were used to predict target relationships in ceRNA networks. qRT-PCR was used to verify our data.ResultsDifferential expression of ceRNAs related to SLE was detected in SLE patients' PBMCs: 644 mRNAs (384 upregulated, 260 downregulated), 326 miRNAs (223 upregulated, 103 downregulated), 221 lncRNAs (79 upregulated, 142 downregulated), and 31 circRNAs (21 upregulated, 10 downregulated). We drew ceRNA signalling networks made up of the differentially expressed mRNAs/miRNAs/lncRNAs/circRNAs mentioned above, and the hub genes included IRF5, IFNAR2, TLR7, IRAK4, STAT1, STAT2, C2, and Tyk2. These hub genes were involved in ceRNA signalling pathways, such as the IL-17 signalling pathway and type I interferon signalling pathway.ConclusionsWe explored the differential expression profiles of various kinds of ceRNAs and integrated signalling networks constructed by ceRNAs. Our findings offer new insights into the pathogenesis of SLE and hint at therapeutic strategies.

Project description:Background:Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression in the immune system, but their impact on neuropsychiatric systemic lupus erythematosus (NPSLE) remains unknown. Methods:RNA sequencing analysis was used to screen the comprehensive expression profile of lncRNAs and messenger RNAs (mRNAs) in peripheral blood mononuclear cells (PBMCs) from NPSLE patients, active SLE patients who had never experienced neuropsychiatric manifestations (Non-NPSLE) and healthy controls. Differentially expressed (DE) lncRNA levels were validated by qRT-PCR in 26 NPSLE patients, 31 Non-NPSLE patients and 30 healthy controls. Further, correlations of DE lncRNAs with clinical manifestations of NPSLE patients were analyzed. Finally, a bioinformatic analysis was performed to investigate the potential functions of DE genes. Results:Four hundred and fifty-one lncRNAs and 272 mRNAs were DE between the NPSLE patients and Non-NPSLE patients, among which, significantly upregulated expression levels of NONHSAT208182.1, NONHSAT182114.1, NONHSAT106801.2, NONHSAT039491.2, ENST00000356215, NONHSAT087499.2 and NONHSAT207026.1 while downregulated expression levels of NONHSAT001281.2 and NONHSAT024353.2 were further validated in PBMCs from NPSLE patients by qRT-PCR. Bioinformatic analysis suggested several gene ontology (GO) terms and signal pathways may play important roles in NPSLE development. Co-expression networks analysis indicated that 170 lncRNAs and 46 mRNAs were included in the co-expression network. The expression level of NONHSAT039491.2 was associated with the activity of SLE and the presence of anti-dsDNA, anti-RNP antibody, dizziness and headache. NONHSAT087499.2 level correlated with anti-RNA antibody, ENST00000356215 level correlated with olfactory threshold and oral ulcer. NONHSAT208182.1 level correlated with the presence of fever, unstable walking and urinary red blood cells. NONHSAT106801.2 correlated with frequency of B cells and the presence of fever. NONHSAT024353.2 level was associated with serum IgG levels and the presence of anti-SSA and disorder of consciousness. Conclusions:Our data provided comprehensive evidence regarding the differential expression of lncRNAs in PBMCs from NPSLE patients, indicating that these DE lncRNAs may play roles in NPSLE development. Our finding shed light on the understanding of the molecular mechanisms of lncRNAs in the pathogenesis of NPSLE.

Project description:ObjectiveThe multisystem involvement and high heterogeneity of systemic lupus erythematosus (SLE) lead to great challenges in its diagnosis and treatment. The purpose of this study was to find new lncRNAs in peripheral blood mononuclear cells of SLE patients by transcriptome sequencing and explore their potential as biomarkers and their correlation with clinical features.Materials and methodsTranscriptome sequencing was used to screen differentially expressed lncRNAs (DELs) and mRNAs (DEMs). The expression of these selected lncRNAs and mRNAs in SLE patients and healthy controls was verified by qPCR. DAVID and WebGestalt were used to perform enrichment analysis. Cytoscape was used to construct a protein-protein network, a coexpression network, and a competitive endogenous RNA network to reveal the regulatory mechanisms of lncRNAs at the transcriptome level.ResultsA total of 1737 DELs and 4078 DEMs were identified between SLE patients and healthy controls. Ten lncRNAs and eight genes were verified by qPCR in a larger sample set. The lncRNA NONHSAT101022.2 was significantly downregulated in SLE patients and was also significantly related to the activity and severity of disease. The upregulated genes were enriched in defense and the immune response, while the downregulated genes were mainly enriched in SLE-related pathways. Topology network analysis revealed that the lncRNAs were involved in regulation at the transcriptome level, including acting directly on mRNA or indirectly affecting gene expression by acting on miRNA.ConclusionIn this work, we identified many mRNAs and novel lncRNAs by transcriptome sequencing. The functions and regulatory mechanisms of these lncRNAs were analyzed by bioinformatic methods. The novel lncRNA NONHSAT101022.2 is significantly downregulated in SLE patients and is significantly related to the activity and severity of disease. Additionally, we propose that NONHSAT101022.2 may enhance the signal transduction of β2-AR by cis regulating LMBRD2, inducing NK cells to produce high levels of IFN-γ and thereby exacerbating SLE.

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Increased expression of hub gene CXCL10 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus.

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Increased expression of hub gene CXCL10 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus.

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