IRAK-M Associates with Susceptibility to Adult-Onset Asthma and Promotes Chronic Airway Inflammation

IL-1R-associated kinase (IRAK)-M regulates lung immunity during asthmatic airway inflammation. However, the regulatory effect of IRAK-M differs when airway inflammation persists. A positive association between IRAK-M polymorphisms with childhood asthma has been reported. In this study, we investigated the role of IRAK-M in the susceptibility to adult-onset asthma and in chronic airway inflammation using an animal model. Through genetic analysis of IRAK-M polymorphisms in a cohort of adult-onset asthma patients of Chinese Han ethnicity, we identified two IRAK-M single nucleotide polymorphisms, rs1624395 and rs1370128, genetically associated with adult-onset asthma. Functionally, the top-associated rs1624395, with an enhanced affinity to the transcription factor c-Jun, was associated with a higher expression of IRAK-M mRNA in blood monocytes. In contrast to the protective effect of IRAK-M in acute asthmatic inflammation, we found a provoking impact of IRAK-M on chronic asthmatic inflammation. Following chronic OVA stimulation, IRAK-M knockout (KO) mice presented with significantly less inflammatory cells, a lower Th2 cytokine level, a higher IFN-gamma concentration, and increased percentage of Th1 cells in the lung tissue than wild type mice. Moreover, lung dendritic cells (DC) from OVA-treated IRAK-M KO mice expressed a higher percentage of costimulatory molecules PD-L1 and PD-L2. Mechanistically, in vitro TLR ligation led to a greater IFN-gamma production by IRAK-M KO DCs than wild type DCs. These findings demonstrated a distinctive role of IRAK-M in maintaining chronic Th2 airway inflammation via inhibiting the DC-mediated Th1 activation and indicated a complex role for IRAK-M in the initiation and progression of experimental allergic asthma.