IL-1R and IL-1RA differentially contribute to immunopathogenesis during fungal asthma

Abstract

Abstract Severe asthma with fungal sensitization defines a subset of asthmatics with allergy to multiple fungal species, including Aspergillus fumigatus. We have previously shown genetic deficiency in or neutralization of IL-22 improves fungal asthma severity, which correlated with lower levels of IL-1α and IL-1β. Here, we show that bronchoalveolar lavage fluid (BALF) and induced sputum from human asthmatics sensitized to fungi demonstrate increased levels of IL-1α, IL-1β and IL-1 Receptor Antagonist (IL-1RA) compared to fungal negative asthmatics, suggesting that members of the IL-1 cytokine family may contribute to fungal asthma severity. To this end, we examined fungal asthma severity in mice deficient in IL-1R and IL-1RA with the hypothesis being that severity would be decreased and increased in these animals respectively. Surprisingly, the absence of IL-1R signaling had no impact on biomarkers of asthma severity (i.e. levels of proallergic CCL17, CCL22, and IL-33), yet Il1r−/−mice demonstrated better lung function compared to WT mice. Interestingly, the absence of IL-1R signaling resulted in a profound defect in the production of IL-22, suggesting a mechanism of improved lung function in Il1r−/− mice. In direct contrast, Il1rn−/− mice exhibited elevated proallergic biomarker levels, but no changes in the levels of IL-22. These preliminary results identify differential roles for IL-1R signaling (IL-22 mediated immunopathogenesis) and IL-1RA signaling (type 2 mediated immunopathogenesis) in fungal asthma severity.