Erythromycin inhibits neutrophil extracellular traps in smoking-related chronic pulmonary inflammation

Neutrophil extracellular traps (NETs) may play a critical role in initiation of adaptive immunity in smoking-related chronic airway inflammation. Erythromycin ameliorates airway neutrophilic inflammation in COPD. However, the effect of erythromycin on NETs induced by cigarette smoke is unknown. NETs in sputum of COPD and healthy controls were assessed. NETs stimulated-MoDCs were co-cultured with native T cells. human or mouse neutrophils were exposed to CSE in the presence of erythromycin. Further, mice were chronically exposed to cigarette smoke with erythromycin treatment. NETs, Th1 and Th17 cells and the activation of myeloid dendritic cells (mDCs) were analysed. NETs were increased in the sputum of COPD patients. The levels of NET-DNA were correlated with the Th1 response, the activation of mDCs and airflow limitation. In vitro, CSE-induced NETs could activate moDCs and promote Th1 and Th17 differentiation. Erythromycin effectively inhibited CSE-induced NETs through suppressing NET-associated neutrophil elastase and myeloperoxidase. In vivo, erythromycin decreased NETs in the airway and ameliorated emphysema in mice exposed to cigarette smoke, which was accompanied by the down-regulation of Th1 and Th17 cells and the suppression of CD40⁺ and CD86⁺ mDCs. These findings provide direct evidence that erythromycin is a potential therapeutic strategy for NETs in smoking–related chronic lung inflammation.