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

Abstract

Rationale: Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1b secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1b 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, eDNAhigh 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-1b (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.

Neutrophil calprotectin identifies severe pulmonary disease in COVID-19

“…NETs are extracellular webs of DNA, histones, and microbicidal proteins that appear to perpetuate many types of lung disease including smoking-related disease (41), cystic fibrosis (42), and ARDS (14,43,44). NETs leverage calprotectin as an antimicrobial strategy against Candida (45) and Aspergillus (46), but, when left unchecked, NETs are also an important source of macrophage activation (47,48) and microvascular occlusion (49,50). This is another topic that in our opinion requires further and urgent investigation.…”

Targeting potential drivers of COVID-19: Neutrophil extracellular traps

“…Together, these data suggest that under conditions in which the normal signals to dampen inflammation are lost, such as during a cytokine storm, a signaling loop between macrophages and neutrophils can lead to uncontrollable, progressive inflammation. Indeed, a correlation between NETs and IL1β exists in severe asthma (Lachowicz-Scroggins et al, 2019). If a NET–IL1β loop is activated in severe COVID-19, the accelerated production of NETs and IL1β could accelerate respiratory decompensation, the formation of microthrombi, and aberrant immune responses.…”

“…NETs can be detected in tissues by immunohistochemistry and in blood by sandwich ELISA (Caudrillier et al, 2012; Jiménez-Alcázar et al, 2017; Lachowicz-Scroggins et al, 2019; Park et al, 2016). As samples from patients become available, it will therefore be possible to determine whether the presence of NETs is associated with severe COVID-19.…”

Neutrophil extracellular traps in COVID-19

“…Although it has yet to be assessed whether NETs contribute to the inflammatory storm that leads to respiratory failure in many COVID-19 patients, there is emerging evidence to implicate inflammatory cytokines such as interleukin (IL)-1β and IL-6 in the COVID-19 milieu (17). Not surprisingly, NETs are intimately intertwined with both cytokines, and especially IL-1β, in many pulmonary and cardiovascular diseases (8,(18)(19)(20)(21)(22)(23).…”