Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma

Summary Background Autophagy and neutrophil extracellular DNA traps ( NET s) are implicated in asthma; however, their roles in asthma pathogenesis have not been elucidated. Objectives We compared autophagy and NET production levels from peripheral blood neutrophils ( PBN s) of patients with severe asthma ( SA ) and non‐severe asthma ( NSA ). Additionally, we investigated the inflammatory effects of NET s on human airway epithelial cells ( AEC s) and peripheral blood eosinophils ( PBE s). Methods Peripheral blood neutrophils from patients with SA ( n = 30) and NSA ( n = 38) were treated with interleukin ( IL )‐8 (100 ng/mL). Autophagy (light chain 3‐ II expression) and NET production levels were evaluated by Western blot, immunofluorescence microscopy, and PicoGreen assay. The effects of NET s on AEC s were assessed by investigating cell death, cell detachment, expression of occludin and claudin‐1, and IL ‐8 production; the effects of NET s on PBE s were examined by investigating the activation and release of eosinophil cationic protein ( ECP ) and eosinophil‐derived neurotoxin ( EDN ). Results Untreated and IL ‐8‐treated PBN s from the SA group produced higher autophagy and NET levels compared with those from the NSA group ( P < 0.01). IL ‐8 increased autophagy and NET levels in PBN s from the SA group, but not from the NSA group. NET levels were correlated with autophagy levels in PBN s ( P < 0.001). IL ‐8‐induced NET production levels negatively were correlated with FEV 1/ FVC ( r = −0.700, P = 0.016). NET s induced cell death, detachment, degradation of occludin and claudin‐1, and IL ‐8 production from AEC s. Higher levels of NET ‐induced ECP and EDN were released from PBE s in SA compared with NSA groups. Conclusions and Clinical Relevance Neutrophil autophagy and NET s could enhance asthma severity by damaging airway epithelium and triggering inflammatory responses of AEC s and PBE s. Modulating neutrophil autophagy and NET production may be a new target therapy for SA .