Allergen-induced vital DNA release by the airway epithelium amplifies type-2 immunity

ABSTRACT: This study has several novel aspects that address molecular mechanisms underlying type 2 immunity and allergic inflammation. We have identified a previously unknown response of human airway epithelial cells to allergens that involves rapid mobilization and release of nuclear DNA (nDNA) from epithelial cells that remain viable throughout the duration of exposure. We show that nDNA release occurs across the apical membrane, but not the basolateral membrane and that sequence analysis of the secreted DNA reveals proportionally higher amounts of promotor and exon sequences and lower intron and intergenic sequences compared to the normal distributions of these regions in the intact genome. Furthermore, unlike DNA release during NETosis, the extracellular DNA is highly fragmented, ranging in size from 1000-5000 bp. We discovered that allergen exposure stimulates caspase 3 by a non-canonical mechanism involving calcium-dependent activation of furin and that caspase 3 activity leads to DNA fragmentation as shown in comet assays. Using a mouse model of allergic inflammation, we demonstrate that allergen-induced type 2 immune responses are markedly reduced by pretreatment with a DNA scavenger and that nDNA release was significantly reduced in mice that were caspase 3 deficient. Moreover, we show that intranasal treatment with mouse genomic DNA combined with submaximal exposure to allergens amplified secretion of Th2 cytokines into bronchoalveolar lavage fluid while DNA alone had no effect. These results highlight a novel, allergen-dependent mechanism of regulated and rapid nDNA mobilization and release that amplifies type 2 immunity in airways and suggests that pharmacotherapies targeting this mechanism may be beneficial in reducing allergic inflammation and exacerbation of asthma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198721 | GEO | 2022/10/01

REPOSITORIES: GEO