Therapeutic and prophylactic deletion of IL-4Ra-signaling ameliorates established ovalbumin induced allergic asthma

Abstract

Background: Allergic asthma is a chronic inflammatory airway disease driven predominantly by a TH2 immune response to environmental allergens. IL-4Rα-signaling is essential for driving TH2-type immunity to allergens. Anti-TH2 therapies have the potential to effectively reduce airway obstruction and inflammation in allergic asthma. Objective: We investigated potential therapeutic effects of selective inhibition of this pathway in mice with established allergic airway disease. We further investigated whether IL-4Rα disruption in systemically sensitized mice can prevent the onset of the disease. Methods: We used RosacreERT2IL-4Rα−/lox mice, a tamoxifen (TAM)-inducible IL-4Rα knockdown model to investigate the role of IL-4/IL-13 signaling prior to the onset of the disease and during the effector phase in the ovalbumin-induced allergic airway disease. Results: Inducible deletion of IL-4Rα demonstrated therapeutic effects, on established allergic airway disease, and prevented the development of ovalbumin-induced airway hyperreactivity, eosinophilia, and goblet cell metaplasia in allergen-sensitized mice. Interestingly, IL-4Rα knockdown after allergic sensitization did not induce TH17, a neutrophilic inflammatory response as observed in global IL-4Rα-deficient mice after intranasal allergen challenge. Conclusion: Abrogation of IL-4Rα signaling after allergic sensitization would have significant therapeutic benefit for TH2-type allergic asthma.