SARS-CoV-2 induces "cytokine storm" hyperinflammatory responses in RA patients through pyroptosis.
The coronavirus disease (COVID-19) is a pandemic disease that threatens worldwide public health, and rheumatoid arthritis (RA) is the most common autoimmune disease. COVID-19 and RA are each strong risk factors for the other, but their molecular mechanisms are unclear. This study aims to investigate the biomarkers between COVID-19 and RA from the mechanism of pyroptosis and find effective disease-targeting drugs.
We obtained the common gene shared by COVID-19, RA (GSE55235), and pyroptosis using bioinformatics analysis and then did the principal component analysis(PCA). The Co-genes were evaluated by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ClueGO for functional enrichment, the protein-protein interaction (PPI) network was built by STRING, and the k-means machine learning algorithm was employed for cluster analysis. Modular analysis utilizing Cytoscape to identify hub genes, functional enrichment analysis with Metascape and GeneMANIA, and NetworkAnalyst for gene-drug prediction. Network pharmacology analysis was performed to identify target drug-related genes intersecting with COVID-19, RA, and pyroptosis to acquire Co-hub genes and construct transcription factor (TF)-hub genes and miRNA-hub genes networks by NetworkAnalyst. The Co-hub genes were validated using GSE55457 and GSE93272 to acquire the Key gene, and their efficacy was assessed using receiver operating curves (ROC); SPEED2 was then used to determine the upstream pathway. Immune cell infiltration was analyzed using CIBERSORT and validated by the HPA database. Molecular docking, molecular dynamics simulation, and molecular mechanics-generalized born surface area (MM-GBSA) were used to explore and validate drug-gene relationships through computer-aided drug design.
COVID-19, RA, and pyroptosis-related genes were enriched in pyroptosis and pro-inflammatory pathways(the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex, death-inducing signaling complex, regulation of interleukin production), natural immune pathways (Network map of SARS-CoV-2 signaling pathway, activation of NLRP3 inflammasome by SARS-CoV-2) and COVID-19-and RA-related cytokine storm pathways (IL, nuclear factor-kappa B (NF-κB), TNF signaling pathway and regulation of cytokine-mediated signaling). Of these, CASP1 is the most involved pathway and is closely related to minocycline. YY1, hsa-mir-429, and hsa-mir-34a-5p play an important role in the expression of CASP1. Monocytes are high-caspase-1-expressing sentinel cells. Minocycline can generate a highly stable state for biochemical activity by docking closely with the active region of caspase-1.
Caspase-1 is a common biomarker for COVID-19, RA, and pyroptosis, and it may be an important mediator of the excessive inflammatory response induced by SARS-CoV-2 in RA patients through pyroptosis. Minocycline may counteract cytokine storm inflammation in patients with COVID-19 combined with RA by inhibiting caspase-1 expression.
Zheng Q
，Lin R
，Chen Y
，Lv Q
，Zhang J
，Zhai J
，Xu W
，Wang W
... -
《Frontiers in Immunology》
Identification of potential ferroptosis-associated biomarkers in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and gradual joint degeneration, resulting in function disability. Recently, ferroptosis, a novel form of regulated cell death that involves iron-dependent lipid peroxidation, has been implicated in the pathogenesis of RA. However, the underlying molecular mechanisms and key genes involved in ferroptosis in RA remain largely unknown.
The GSE134420 and GSE77298 datasets were downloaded and DEGs were identified using R software. The DEGs were then mapped to the dataset of 619 ferroptosis-related genes obtained from the GeneCards database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to investigate the possible biological functions. Protein-protein interaction (PPI) networks were constructed to identify the hub genes. The relationship between hub genes and immune infiltration was estimated using the CIBERSORT algorithms. Gene Set Enrichment Analysis (GSEA) was used to explore the underlying signaling pathways of hub genes. Genome-wide association studies (GWAS) analysis was performed to confirm the pathogenic regions of the hub genes. RcisTarget and Gene-motif ranking databases were used to identify transcription factors (TFs) associated with the hub genes. The miRcode databases were utilized to construct the microRNA (miRNA)-messenger RNA (mRNA) network. Single-cell analysis was utilized to cluster cells and display the expression of hub genes in cell clusters. Finally, the expression and potential mechanism of hub genes were investigated in human and experimental samples.
Three hub genes PTGS2, ENO1, and GRN highly associated with ferroptosis were identified. Four pathogenic genes HLA-B, MIF, PSTPIP, TLR1 were identified that were significantly and positively correlated with the expression levels of hub genes. The results of the GSEA showed that the hub genes were significantly enriched in pathways related to immunity, lysosome, phagocytosis and infection. ENO1 and PTGS2 were enriched in the TF-binding motif of cisbp_M5493. The hub genes were validated in experimental and patient samples and highly level of ENO1 expression was found to inhibit ACO1, which reduces ferroptosis in proliferating fibroblast-like synoviocytes (FLS).
PTGS2, ENO1 and GRN were identified and validated as potential ferroptosis-related biomarkers. Our work first revealed that ENO1 is highly expressed in RA synovium and that ferroptosis may be regulated by the ENO1-ACO1 axis, advancing the understanding of the underlying ferroptosis-related mechanisms of synovial proliferation and providing potential diagnostic and therapeutic targets for RA.
He X
，Zhang J
，Gong M
，Gu Y
，Dong B
，Pang X
，Zhang C
，Cui Y
... -
《Frontiers in Immunology》
Identification of potential ferroptosis key genes and immune infiltration in rheumatoid arthritis by integrated bioinformatics analysis.
Ferroptosis is of vital importance in the development of Rheumatoid arthritis (RA). The purpose of this project is to clarify the potential ferroptosis-related genes, pathways, and immune infiltration in RA by bioinformatics analysis.
We acquired ferroptosis-related genes (FRGs) from Ferroptosis database (FerrDb). We obtained the Gene dataset of RA (GSE55235) from the Gene Expression Omnibus (GEO) Database, screened the differentially expressed genes (DEGs) in RA and control samples, and then took the intersection of it and FRGs. Aiming to construct the protein-protein interaction (PPI) networks of the FRGs-DEGs, STRING database and Cytoscape software 3.7.0 would be used. Furthermore, hub genes were identified by CytoNCA, a Cytoscape plug-in. The gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of FRGs-DEGs were performed.
We identified 34 FRGs-DEGs, including 7 upregulated and 27 downregulated genes by taking the intersection of the FRGs and DEGs. PPI analysis identified a total of 3 hub genes(VEGFA, PTGS2, and JUN). GO enrichment analyses and KEGG Pathway enrichment displayed that the FRGs-DEGs are involved in the response to oxidative stress and corticosteroid, heme binding, FoxO-signal pathway. Results of immune infiltration displayed that increased infiltration of T cells, while Macrophages M2 less may be related to the occurrence of RA.
The hub genes involved in ferroptosis in RA may be VEGFA, PTGS2, and JUN, which are mainly involved in FoxO-signal pathway. T cell, Mac, and plasma cells may be involved in the regulation of RA-joints-synovial-inflammation.
Fan Y
，Li Y
，Fu X
，Peng J
，Chen Y
，Chen T
，Zhang D
... -
《Heliyon》
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