SARS-CoV-2 induces “cytokine storm” hyperinflammatory responses in RA patients through pyroptosis

Abstract

BackgroundThe 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.MethodsWe 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.ResultsCOVID-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.ConclusionsCaspase-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.

Bioinformatics and system biology approach to identify the influences of SARS-CoV-2 on metabolic unhealthy obese patients

“…JUN is a subunit of activating protein 1, an inducible transcription factor composed of multiple protein complexes, that plays a role in several types of cell differentiation and inflammation ( Chang et al, 2013 ). Moreover, CASP1 is the most involved pathway in cytokine storm, and YY1 is a crucial TF in CASP1 expression ( Zheng et al, 2022 ). In obese mouse models, YY1 was markedly upregulated ( Lu et al, 2014 ), which may provide us with the possible cause of increased mortality in COVID-19 patients with MUO.…”

Bioinformatics and system biology approach to identify the influences of COVID-19 on metabolic unhealthy obese patients

“…Furthermore, cytokines storm is the main risk factor that leads to the death outcome of COVID-19 patients. CASP1 is the most involved pathway in cytokine storm, and YY1 is a crucial TF in CASP1 expression[34]. In obese mouse models, YY1 was markedly upregulated[35], which may provide us with the underlying cause of increased mortality in COVID-19 patients with MUO.…”

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

“…Apoptosis represents a form of cell death of somatic cells long since known to be associated with abundant translocation of nuclear contents to cell surface blebs and ultimately, to the blood stream ( 195 – 197 ). Even more DAMPs are released when immune cells undergo inflammatory forms of cell death such as pyroptosis ( 22 , 58 , 181 , 198 , 199 ). The DAMP most frequently reported for COVID-19 is lactate dehydrogenase, a central enzyme of anaerobic glycolysis that is present in virtually all cells and that, therefore, reliably indicates cell death when occurring at high concentrations in the extracellular space ( 200 – 202 ).…”

“…In addition, enhanced plasma levels of pyroptosis markers were detected in COVID-19 patients, and the levels of caspase -1 and IL-18 in serum correlated with the degree of COVID-19 severity ( 12 , 22 , 29 , 220 , 221 ), particularly in elderly patients ( 234 ). Neutrophils, macrophages and PBMCs from SARS-CoV-2-infected patients also exhibited active AIM2 or NLRP3 inflammasomes and enhanced expression of ASC-speck protein, caspase 1 or gasdermin-D ( 12 , 13 , 22 , 29 , 199 , 221 , 233 ). Correspondingly, specific inhibition of the NLRP3 inflammasome suppressed immune overactivation and alleviated COVID-19-like pathology in mice ( 235 ).…”