Cadherin-26 drives macrophage alternative activation via suppressing STUB1-mediated IL-4Rα ubiquitination in asthma

IntroductionIL-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. MethodsCDH26 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 Cdh26fl/flLyz2Cre and control mice. Mechanistic experiments included IL-4R degradation and ubiquitination assay, CDH26 co-immunoprecipitation and mass spectrometry analysis. Cdh26 siRNA encapsulated lipid nanoparticles were used to treat the mouse model. ResultsCDH26 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 Cdh26fl/flLyz2Cre mice compared to control mice. Cdh26 deficiency inhibited the expression of M2 markers as well as IL-4R expression in mouse bronchoalveolar lavage macrophages, cultured bone marrow-derived macrophages, and primary lung macrophages. Furthermore, CDH26 knockdown enhanced whereas CDH26 overexpression suppressed IL-4R ubiquitination and proteasomal degradation in vitro. Mechanistically, CDH26 directly interacts with STUB1 and suppresses the binding of STUB1 to IL-4R and subsequent ubiquitination-proteasomal degradation. Cdh26 siRNA encapsulated lipid nanoparticles markedly alleviated airway eosinophilia, mucus metaplasia and macrophage alternative activation in the mouse model. ConclusionsCDH26 interacts with STUB1 and suppresses STUB1-mediated IL-4R ubiquitination-proteasomal degradation, thereby amplifying IL-4R signaling in macrophages in asthma. CDH26 is a potential therapeutic target for asthma. Take-Home MessageMacrophage CDH26 is upregulated in asthma patients, and Cdh26 deficiency suppresses macrophage alternative activation. CDH26 directly interacts with STUB1 and inhibits STUB1-mediated IL-4R ubiquitination and degradation, thus amplifying IL-4R signaling.