Allergen-induced DNA release from airway epithelium amplifies type-2 immunity
Published: October 25, 2022
Allergic diseases and asthma are often exacerbated by exposure to environmental allergens. However, the underlying mechanisms responsible for amplification of type 2 immune responses and exacerbation of the disease are poorly understood. Previously, a significant correlation was discovered between DNA release and exacerbation of type 2 inflammation in humans following rhinovirus infection. In mice, rhinovirus exposure induced DNA release from neutrophils and possibly other cell types and degrading DNA with DNase blocked exacerbation of the type 2 inflammatory response. Similarly, in patients with treatment-resistant severe asthma, airway inflammation was associated with extracellular DNA within bronchial biopsies or sputum specimens, which correlates with decreases in lung function and asthma control. Therefore, extracellular self-DNA may promote allergic inflammation and represents a potential therapeutic target. However, the cell types and mechanisms involved in DNA release have not been fully characterized.
Recently, a study by Srisomboon et al. published in The Journal of Allergy and Clinical Immunology (JACI), showed that bronchial epithelial cells rapidly (within minutes after exposure) release DNA fragments in response to fungal (Alternaria alternata) and house dust mite (HDM) allergen exposure. The authors tested the hypothesis that allergen-evoked DNA release represents an innate, epithelial response that evolved as a means of amplifying inflammation through activation of self-DNA signaling pathways in immune cells.
Experiments revealed that Alternaria-induced oxidative stress stimulated the release of genomic and mitochondrial DNA from human bronchial epithelial cells by a regulated mechanism, allowing the epithelium to maintain barrier function. Mechanistically, processing of genomic DNA for extracellular release was dependent on activation of caspase 3 by a non-canonical, calcium-dependent mechanism involving cleavage by the pro-protein convertase enzyme furin. Sequencing of extracellular DNA fragments showed disproportionally greater levels of promotor and exon sequences and fewer intron and intergenic regions compared to predictions of random DNA fragmentation. In mouse models, intranasal administration of a DNA scavenger into the airways reduced Alternaria-induced type-2 immune responses. Furthermore, intranasal administration of mouse genomic DNA along with Alternaria amplified activation of group 2 innate lymphoid cells and IL-5 and IL-13 secretion into BAL fluid, whereas DNA alone had no effect.
It is worth noting that allergen-induced DNA release described in this study is distinct from DNA ejection by ETosis, where long filaments of genomic DNA released by certain immune cells play a role in antimicrobial defense. Instead, extracellular genomic DNA and mitochondrial DNA fragments serve as “danger signals” that amplify type 2 immune responses and promote allergic inflammation. Therapies or pharmacologic agents that reduce levels of extracellular DNA may have therapeutic benefits in the treatment of asthma and related diseases.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.
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