Resistin-like molecule-β negatively regulates chronic features of fungal asthma

Abstract

Abstract Severe asthma with fungal sensitization (SAFS) is a subtype of asthma with high incidence in which patients are often therapy-resistant and have chronic disease features such as airway wall remodeling. Shared embryonic, immunologic, and microbiomic lineages of the gut-lung axis should be considered in disease pathogenesis investigations. A resistin family hormone, RELM-β, has been implicated in regulation of mucus production, immune responses, and bacterial colonization in the gut. RELM-β has been previously shown to increase macrophagic inflammation, goblet cell (GC) metaplasia, and fibrosis in mouse models. Since fungal asthma has unique early- and late-phase responses, we investigated the functions of RELM-β in our well-established model of SAFS utilizing Retnlb-null (KO) mice. Characteristics of SAFS developed in KO mice with some differences from wild-type (WT) controls. Kinetics of airway inflammation were delayed in KO although tissue inflammation was similar to WT. GCs interspersing the bronchial epithelia were similar, however, hyperexpression of Muc5ac and Muc5b in KO mice suggests of an altered mucin composition. Subepithelial fibrosis and airway resistance were markedly increased at late timepoints in KO mice compared to WT, indicating that RELM-β inhibits lung fibrosis. RELM-β may function as a homeostatic regulator of B cells since naïve KO mice had elevated systemic IgA. Related molecule, RELM-α, did not increase in KO mice although antimicrobial peptide Camp, Il13, and Tlr4 were hyperexpressed in lungs of these mice. Cumulatively, these data suggest that RELM-β is a regulator of allergic responses and that these effects may occur through direct/indirect mechanisms.