TNFAIP3, PADI4, and CXCR4 as biomarkers of neutrophil extracellular traps in severe asthma.

Asthma is a heterogeneous condition impacting an estimated 300 million individuals globally. Although inhaled corticosteroids are effective in alleviating asthma symptoms, approximately 22 % - 60 % of patients still experience poor disease control. Among these patients, the majority exhibit abnormalities in neutrophils. Studies have shown that neutrophil extracellular traps (NETs) are a neutrophil-specific biological feature and play an important role in asthma pathogenesis. Therefore, we used bioinformatics approaches to identify biomarkers associated with NETs and asthma. Using machine-learning algorithms, we identified Tumor Necrosis Factor Alpha-Induced Protein 3 (TNFAIP3), C-X-C Chemokine Receptor Type 4 (CXCR4), and Protein-Arginine Deiminase Type-4 (PADI4) as potential biomarkers associated with severe asthma and NETs. Immune cell infiltration analysis revealed a strong correlation between these gene expressions and immune cell activation, particularly their roles in neutrophil activation. ROC analysis confirmed the diagnostic efficacy of TNFAIP3, CXCR4, and PADI4 in asthma. Experimental results showed that the expression levels of CXCR4, PADI4, and TNFAIP3 were upregulated in neutrophils from patients with severe asthma. ELISA and other experimental analyses demonstrated that CXCR4 and PADI4 promote the formation of NETs, whereas TNFAIP3 inhibits their generation. Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon primarily derived from smoked foods and air pollution. Molecular docking showed that BaP can stably bind to TNFAIP3, CXCR4, and PADI4. Further investigations revealed that BAP ultimately enhances NETs formation by acting on CXCR4, PADI4, and TNFAIP3. In summary, this study provides potential theoretical guidance for the prevention and management of asthma.