Rationale: Extracellular
DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate
inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in
asthma is uncertain. Objectives: To characterize the role of activated neutrophils in severe
asthma through measurement of NETs and
inflammasome activation. Methods: We measured sputum eDNA in induced sputum from 399 patients with
asthma in the Severe
Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with
asthma into eDNA-low and -high subgroups to compare outcomes of
asthma severity and of neutrophil and
inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by
DNase. Measurements and Main Results: We found that 13% of the Severe
Asthma Research Program-3 cohort is "eDNA-high," as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with
asthma, eDNA-high patients had lower
Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral
corticosteroids for maintenance of
asthma control (all P values <0.05). Sputum eDNA in
asthma was associated with airway neutrophilic
inflammation, increases in soluble NET components, and increases in
caspase 1 activity and IL-1β (all P values <0.001). In in vitro studies, NETs caused cytotoxicity in airway epithelial cells that was prevented by disruption of NETs with
DNase. Conclusions: High extracellular
DNA concentrations in sputum mark a subset of patients with more severe
asthma who have NETs and markers of
inflammasome activation in their airways.