Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation

Abstract

Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of type 2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type 2 responses is poorly understood. We report a significant correlation between release of host double stranded DNA (dsDNA) following rhinovirus infection and exacerbation of type 2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with neutrophil extracellular traps (NETs) formation (NETosis). We further demonstrate that inhibiting NETosis by blocking neutrophil elastase, or degrading NETs with DNase protects mice from type 2 immunopathology. Furthermore, injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type 2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.

LL‐37 promotes neutrophil extracellular trap formation in chronic rhinosinusitis with nasal polyps

“…It is possible for NETs to serve as double‐edged swords, acting as effective antimicrobial defences, but also as putative sources of proteases and other proteins with proinflammatory roles that may promote tissue damage . For example, Park et al demonstrated that NETs induced primary small airway epithelial cell death and degradation of tight junction protein ex vivo.…”

“…Respiratory viral infections are often implicated in CRS exacerbation . For example, Toussaint et al reported rhinovirus infection triggered dsDNA release associated with the NET formation in a mouse model of allergic airway hypersensitivity and showed a significant correlation between the release of host dsDNA after rhinovirus infection and the exacerbation of type‐2 allergic inflammation in humans. Our findings, together with these reports, indicate LL‐37‐induced NETs may play an critical role in the neutrophilic inflammation in CRSwNP.…”

Advances in environmental and occupational disorders in 2016

“…Toussaint et al used a mouse model to demonstrate that rhinovirus infections triggered the formation of neutrophil extracellular traps (NETs), and that blocking this NETosis protects mice from type-2 immunopathology. (48) Future research will likely focus on continued efforts to disrupt the viral and allergen connection with a goal of improving asthma outcomes.…”

Adenosine from a biologic source regulates neutrophil extracellular traps (NETs)

“…In response to inflammatory triggers, neutrophils expel their chromatin coated with effector molecules into the extracellular space . This inflammatory process of neutrophil extracellular trap (NET) formation evolved to contain infectious pathogens, but has been linked to autoimmune, thrombotic, malignant, and inflammatory disorders . NETs contain chromatin, histones, and neutrophil‐derived antibiotic, proteolytic, and proinflammatory molecules that include neutrophil elastase and myeloperoxidase (MPO).…”