Epithelial FETUB-mediated the inhibition of NEP activity aggravates asthma

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-09 DOI:10.1016/j.intimp.2025.114397

Peng Sun , Qi Hua , Heng Fu , Lei Yao , Xijing Yuan , Qian Li , Yuebei Li , Man Jia , Rong Xia , Xin Yao

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引用次数: 0

Abstract

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, FEV₁ and FEV₁%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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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.