IRAK-M knockout promotes allergic airway inflammation, but not airway hyperresponsiveness, in house dust mite-induced experimental asthma model

Abstract

Background: IL-1 receptor associated-kinase (IRAK)-M, expressed by airway epithelium and macrophages, was shown to regulate acute and chronic airway inflammation exhibiting a biphasic response in an OVA-based animal model. House dust mite (HDM) is a common real-life aeroallergen highly relevant to asthma pathogenesis. The role of IRAK-M in HDM-induced asthma remains unknown. This study was aimed to investigate the effect of IRAK-M on allergic airway inflammation induced by HDM using IRAK-M knockout (KO) mice and the potential underlying mechanisms. Methods: IRAK-M KO and wild-type (WT) mice were sensitized and challenged with HDM. The differences in airway inflammation were evaluated 24 hours after the last challenge between the two genotypes of mice using a number of cellular and molecular biological techniques. In vitro mechanistic investigation was also involved. Results: Lung expression of IRAK-M was significantly upregulated by HDM in the WT mice. Compared with the WT controls, HDM-treated IRAK-M KO mice showed exacerbated infiltration of inflammatory cells, particularly Th2 cells, in the airways and mucus overproduction, higher epithelial mediators IL-25, IL- 33 and TSLP and Th2 cytokines in bronchoalveolar lavage (BAL) fluid. Lung IRAK-M KO macrophages expressed higher percentage of costimulatory molecules OX40L and CD 80 and exhibited enhanced antigen uptake. However, IRAK-M KO didn't impact the airway hyperreactivity (AHR) indirectly induced by HDM. Conclusions: The findings indicate that IRAK-M protects allergic airway inflammation, not AHR, by modifying activation and antigen uptake of lung macrophages following HDM stimulation. Optimal regulation of IRAK-M might indicate an intriguing therapeutic avenue for allergic airway inflammation.