Multiomics analysis of neutrophils in SLE: insights from adult and pediatric disease

Neutrophils contribute to systemic lupus erythematosus (SLE) pathogenesis through ROS and NET production, and increased apoptotic debris which causes autoantibody production and immune complex formation. These processes drive inflammation and tissue damage. The aim of this study was to perform integrated transcriptomic and metabolomic analyses comparing paediatric and adult SLE neutrophils. Adult (aSLE) and pediatric (jSLE) patient and healthy adult (HA) and juvenile (HJ) control neutrophils were subjected to RNAseq and 1H-NMR metabolomics. Univariate, multivariate and multiomics enrichment analyses were conducted in R and with Ingenuity Pathway Analysis (IPA). Transcriptomic analysis revealed distinct gene expression profiles. Adult and juvenile SLE neutrophils were enriched for genes regulating IFN-α/β signalling, neutrophil degranulation and NET signalling pathways (IPA, adj.p-value<0.01). Gene Ontology analysis revealed enrichment in cell cycle and interferon signalling in aSLE, and angiogenesis and tissue-specific development in jSLE. Metabolomic profiling identified distinct metabolic alterations in aSLE, with a greater complexity of metabolic changes in jSLE. Multivariate PLS-DA demonstrated group discrimination, particularly in aSLE (balanced accuracy 80%, sensitivity 80%). VIP>1 metabolites were enriched in taurine/hypotaurine and amino acid metabolism in aSLE. Integrating transcriptomic and metabolomic data strengthened IFN-α/β signalling, neutrophil degranulation and NET signalling (adj. p <0.001). Additional metabolic pathways uniquely down-regulated in aSLE included glutamate and glutamine metabolism, nucleotide biosynthesis and tryptophan catabolism (adj.p<0.01). In summary, neutrophils from SLE patients, especially in jSLE, displayed complex transcriptomic and metabolic profiles, with aberrant IFN responses and neutrophil activation.