Cadherin-26 drives macrophage alternative activation via suppressing STUB1-mediated IL-4Rα ubiquitination in asthma
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This article is not in any list yet, why not save it to one of your lists.Abstract
IL-4 receptor (IL-4R)-mediated alternative activation of macrophage drives type 2 airway inflammation. Cadherin-26 (CDH26) upregulates epithelial type II IL-4R signaling in asthma. However, whether CDH26 contributes to type I IL-4R-mediated macrophage activation and the mechanism by which CDH26 upregulates IL-4R expression remains unknown.
Methods
CDH26 expression in bronchoalveolar lavage cells of asthma patients was examined using quantitative PCR and immunostaining. Airway inflammation and macrophage activation were assessed in ovalbumin-sensitized and challenged Cdh26 fl/fl Lyz2Cre and control mice. Mechanistic experiments included IL-4Rα degradation and ubiquitination assay, CDH26 co-immunoprecipitation and mass spectrometry analysis. Cdh26 siRNA encapsulated lipid nanoparticles were used to treat the mouse model.
Results
CDH26 expression was enhanced in bronchoalveolar lavage cells from patients with eosinophilic asthma and was localized to macrophages. Airway eosinophilia, mucous cell metaplasia and macrophage alternative activation were significantly suppressed in ovalbumin-challenged Cdh26 fl/fl Lyz2Cre mice compared to control mice. Cdh26 deficiency inhibited the expression of M2 markers as well as IL-4Rα expression in mouse bronchoalveolar lavage macrophages, cultured bone marrow-derived macrophages, and primary lung macrophages. Furthermore, CDH26 knockdown enhanced whereas CDH26 overexpression suppressed IL-4Rα ubiquitination and proteasomal degradation in vitro. Mechanistically, CDH26 directly interacts with STUB1 and suppresses the binding of STUB1 to IL-4Rα and subsequent ubiquitination-proteasomal degradation. Cdh26 siRNA encapsulated lipid nanoparticles markedly alleviated airway eosinophilia, mucus metaplasia and macrophage alternative activation in the mouse model.
Conclusions
CDH26 interacts with STUB1 and suppresses STUB1-mediated IL-4Rα ubiquitination-proteasomal degradation, thereby amplifying IL-4R signaling in macrophages in asthma. CDH26 is a potential therapeutic target for asthma.
Take-Home Message
Macrophage CDH26 is upregulated in asthma patients, and Cdh26 deficiency suppresses macrophage alternative activation. CDH26 directly interacts with STUB1 and inhibits STUB1-mediated IL-4Rα ubiquitination and degradation, thus amplifying IL-4R signaling.
