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

Abstract

RationaleIL-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.ObjectivesTo investigate whether CDH26 promotes macrophage alternative activation via suppressing IL-4Rα ubiquitination-proteasomal degradation.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 macrophage-specificCdh26-deficient mice. Mechanistic experiments included IL-4Rα degradation and ubiquitination assay, CDH26 co-immunoprecipitation and mass spectrometry analysis.Cdh26siRNA encapsulated lipid nanoparticles were used to treat the mouse model.Measurements and ResultsCDH26 expression was enhanced in bronchoalveolar lavage cells from patients with eosinophilic asthma and was localized to lung macrophages. Airway eosinophilia, mucus overproduction and macrophage alternative activation were significantly suppressed in ovalbumin-challenged macrophage-specificCdh26-deficient mice compared to control mice.Cdh26deficiency inhibits IL-4Rα expression and STAT6 phosphorylation in macrophages in vitro. Furthermore, CDH26 knockdown enhances whereas CDH26 overexpression suppresses IL-4Rα ubiquitination and proteasomal degradation. Mechanistically, CDH26 directly interacts with STUB1 and suppresses the binding of STUB1 to IL-4Rα and subsequent ubiquitination-proteasomal degradation.Cdh26siRNA encapsulated lipid nanoparticles markedly alleviate airway inflammation, mucus overproduction and macrophage alternative activation in the mouse model.ConclusionsCDH26 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.At a glance commentaryScientific knowledge on the subjectIL-4R signaling drives macrophage alternative activation, mucous cell metaplasia, and type 2 airway inflammation in asthma, but the regulatory mechanism underlying IL-4R expression remains unclear.What this study adds to the fieldCDH26 expression is enhanced in lung macrophages from patients with eosinophilic asthma. Macrophage-specificCdh26deficiency suppresses macrophage alternative activation and airway eosinophilia in a mouse model of allergic airway inflammation. CDH26 directly interacts with STUB1 and suppresses STUB1-mediated IL-4Rα ubiquitination-proteasomal degradation, resulting in sustained activation of IL-4R signaling. Lipid nanoparticles encapsulatingCdh26siRNA effectively alleviate airway eosinophilia and mucus overproduction in the mouse model.