Background: Neuropeptide accumulation exacerbates asthma, with reduced neprilysin (NEP) activity implicated. However, this regulatory mechanism remains unexplored.
Objective: To identify and characterize epithelial-derived modulators of NEP activity and their role in asthma pathogenesis.
Methods: Bioinformatics and molecular docking identified fetuin B (FETUB) as a NEP inhibitor. FETUB expression in human lung tissue was assessed by immunohistochemistry, and its levels in exhaled breath condensate (EBC) and serum were quantified by ELISA. Functional assays and a lung-specific FETUB knockdown mouse model using Adeno-associated virus (AAV) vector confirmed its role in NEP inhibition and asthma pathogenesis.
Results: Bioinformatic analysis, protein binding assays, and fluorescence substrate degradation experiments confirmed that FETUB is an inhibitor of NEP. Serum FETUB levels were elevated in asthmatics and positively correlated with serum IgE, eosinophil counts. Similarly, in asthmatic EBC, FETUB levels were significantly higher than in healthy controls and negatively correlated with asthma control test, FEV and FEV%pred. The expression of FETUB was elevated in asthma lung tissue and primarily localized to airway epithelial cells. Combined bioinformatics and experimental data indicated that IL-13 as a key inducer of epithelial FETUB expression. Lung-specific FETUB knockdown restored NEP activity, reduced neuropeptides CGRP and SP, and improved airway inflammation and hyperresponsiveness in asthma.
Conclusion: The findings suggest that epithelial-derived FETUB exacerbates airway inflammation and hyperresponsiveness in asthma through the inhibition of NEP activity and the resultant accumulation of CGRP and SP.
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