A Multi-Omics Network Identifies Neutrophil Elastase-Positive Extracellular Vesicles in Plasma of Alpha-1 Antitrypsin Deficient Individuals as Accelerants of Lung Inflammation

ABSTRACT: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in SERPINA1, leading to chronic obstructive pulmonary disease (COPD) and liver disease. Neutrophils are key regulators of inflammatory signaling networks, however, their dysregulation in AATD and associated molecular mechanism are not well understood yet. Herein, we employed a multi-omics approach, integrating RNA sequencing (RNA-seq) and metabolomics, to comprehensively characterize neutrophil dysfunction in AATD. RNA-seq analysis of blood neutrophils from AATD individuals revealed transcriptional dysregulation in the genes highly involved in intracellular signaling cassette, immune response-activating and regulating signaling pathways, and regulation of signal transductions which govern inflammation and metabolic adaptation. Isolation and characterization of neutrophil-derived extracellular vesicles (EV) further demonstrated an increased plasma burden of neutrophil elastase (NE)-rich EV with elevated surface-bound NE. Metabolomic profiling revealed that these EV are enriched with pro-inflammatory metabolites linked to dysregulated signaling pathways. Integrated transcriptomic and metabolomic network analysis revealed that dysregulated neutrophil gene expression and signaling pathways reshape EV metabolic cargo, linking metabolic reprogramming to inflammatory signal transduction in AATD. Moreover, differentially expressed EV metabolites may modulate gene expression in EV recipient cells, further sustaining chronic inflammation in AATD. These findings establish a mechanistic link between neutrophil gene dysregulation and EV-driven inflammatory signaling, revealing how metabolic reprogramming of EV cargo influences cellular crosstalk via cytokine and protease-mediated pathways. The observed upregulation of interferon, pattern recognition receptors, and cytokine-mediated signaling pathways in neutrophils suggests a potential feedback loop amplifying inflammation in AATD and COPD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291638 | GEO | 2026/07/31

REPOSITORIES: GEO