Journal Article

Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma

Lachowicz-Scroggins, Marrah E., Charbit, Annabelle R., Wenzel, Sally E., Fahy, John V., Raymond, Wilfred, Castro, Mario, Hastie, Annette T., Israel, Elliot, Coverstone, Andrea M., Fajt, Merritt L., Johansson, Mats W., Looney, Mark R., Erzurum, Serpil C., Peters, Michael C., Bleecker, Eugene R., Woodruff, Prescott G., Jarjour, Nizar N., Phillips, Brenda R., Gordon, Erin D., Lefrançais, Emma, Dunican, Eleanor M., Comhair, Suzy A., Mauger, David T., Levy, Bruce D.

2019

Overview

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. To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation. 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. 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 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 values <0.001). In studies, NETs caused cytotoxicity in airway epithelial cells that was prevented by disruption of NETs with DNase. 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.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Acute Disease / Adult / Asthma / Asthma - immunology / Asthma - metabolism / Asthma - physiopathology / Biochemistry, Molecular Biology / Blotting, Western / Case-Control Studies / Cell Behavior / Cellular Biology / Dehydrogenases / Deoxyribonucleic acid / DNA / DNA - metabolism / Extracellular Traps / Extracellular Traps - physiology / Female / Gene expression / Glucosephosphate Dehydrogenase / Glucosephosphate Dehydrogenase - metabolism / Human health and pathology / Humans / Immunology / Infectious diseases / Inflammasomes / Inflammasomes - physiology / Inflammation / Innate immunity / Interleukin-6 / Interleukin-6 - metabolism / Interleukin-8 / Interleukin-8 - metabolism / Kinases / Life Sciences / Longitudinal Studies / Male / Middle Aged / Neutrophils / Neutrophils - physiology / Original / Pulmonology and respiratory tract / R&D / Research & development / Tissues and Organs