| BackgroundSystemic lupus erythematosus(SLE)is a multisystem autoimmune disease that results from aberrant immune function.Numerous disorders in the immune system have been described in patients with SLE,including T cells,B cells,monocytes and dendritic cells.These cells lead to T-and B-cell activation,and result in autoantibodies against self-antigens production.The importance of innate immune system has also been emerging with respect to the pathogenesis of SLE.Cells of the mononuclear phagocyte system(MPS)are an integral part of the innate immune system,play essential roles in physiological and pathological processes,including with major roles in regulating the onset,development,and termination of inflammatory diseases.And they actively involved in the development of both chronic inflammation and autoimmune disease.So far,the pathogenesis of SLE has not been fully elucidated and few choices of therapy.Further studies are needed to elucidate the role of MPS in SLE.MethodsMicroarray datasets were downloaded from the Gene Expression Omnibus database.To identify the potential genes involved in mononuclear phagocytes in SLE,we performed a microarray analysis of two data bases.Differentially expressed genes(DEGs)were determined and weighted gene co-expression network analysis(WGCNA)was performed.The functional analysis was performed by Kyoto Encyclopedia of Genes and Genomes(KEGG),Gene Ontology(GO)analyses.According to the specific expressed genes,protein-protein interaction(PPI)networks were built to identify the interactions among genes.The hub genes were screened by Lasso regression analysis.An gene-set enrichment analysis(GSEA)of the hub genes from the pairwise comparison was performed.Then we further analyzed the distribution of hub genes in monocyte subsets by single-cell RNA sequencing(scRNA-seq).ResultsTo address these issues,we performed bioinformatics analysis combined with machine learning algorithms to identify hub genes and pathways in SLE mononuclear phagocytic system.First,DEGs shared by the two DEG sets were screened and then co-expression network analysis was performed on these genes expression profiles with weighted gene co-expression network analysis to explore co-expression modules in SLE mononuclear phagocytes.28 candidate genes were found.GO showed that these altered genes are enriched in the cytokine-mediated signaling pathway,interferon signaling pathway,etc.As for KEGG pathway analysis,these genes were mostly associated with NOD-like receptor signaling pathway and cytosolic DNA-sensing pathway.In order to further screen candidate genes,PPI were established using STRING.The protein nodes that have no interaction with other proteins were removed.The Lasso regression analysis were further conducted to identify the hub genes in the network.The 4 hub genes were IFIT3,OAS3,SAMD9 and XAF1.To explore hug genes related signaling pathways,GSEA was conducted,suggesting that the hug genes were linked to JAK-STAT signaling pathway and Toll-like receptor signaling pathway.Finally,single-cell mRNA-sequencing data from the peripheral blood mononuclear were queried as to cell types expressing these 4 hub genes.We found that IFIT3,OAS3 and SAMD9 associated with CD 14 monocytes and XAF1 associated with plasmacytoid dendritic cell.GO and KEGG analysis was performed in CD14+monocytes and pDC.Both of them were strongly enriched for several immune-related pathways including interferon.The pseudo-temporal ordering analyses of the hub genes were performed.As differentiation progresses,during the differentiation,the expression of IFIT3 was gradually decreased in pDC,and increased in Mac.The expression of OAS3,SAMD9 was gradually decreased in Mac.The expression of XAF1 was gradually increased in pDC and decreased in Mac.ConclusionWe identified the 4 hub genes(IFIT3,OAS3 and SAMD9)for SLE mononuclear phagocytes and associated signaling pathways.The results of the current study provide novel insights into PVR pathogenesis and treatment therapeutic targets. |
PDF Full Text Request