Inhibiting host DNA release prevents mixed neutrophilic/eosinophilic airway inflammation in severe asthma phenotype

Abstract

Abstract Asthma pathophysiology and treatment strategies are predicted by inflammatory phenotypes. Unlike the relatively well-defined mechanisms that result in eosinophilia, those leading to noneosinophilic asthma, particularly non-type 2 neutrophilic/eosinophilic asthma, remain relatively poorly understood. We recently discovered that leukocytes released extracellular traps (ETs) comprising DNA fibers and granule proteins in the BAL fluid of patients with mild asthma who were experimentally challenged with allergen according to the subsegmental bronchoprovocation to allergen (SBP-AG) protocol. Key aspects of ETs in the immune response are sufficient to recapitulate many features of asthma pathophysiology which results in mucus hypersecretion and airway remodeling in the airways of asthmatics. To test hypothesize that inhibiting ET-associated host dsDNA release prevents neutrophilic/eosinophilic airway inflammation in severe asthma (SA) phenotype, we set up the SA mouse model, that mirrors the complex immune response identified in human SA. We showed that host dsDNA and neutrophil elastase were greatly increased in the airways and short noncoding miR-155 contributes to the release of host dsDNA, which exacerbates many features of allergic inflammation. In accordance with what we observed in high miR-155 expression in alveolar macrophages, we also noted that there was markedly less ETs formation in the airways of miR-155fl/flLysMcre mice subjected to the SA model compared with their WT counterparts. In sum, miR-155 engages in the release of host dsDNA that contributes to airway damage and thus promotes mixed granulocytic inflammation.