Neutrophil Elastase Reprograms Macrophage Function in Chronic Obstructive Pulmonary Disease

Background: The relentless progression of lung disease in COPD is due in part to the failure of lung macrophage innate immune function. The failure of the macrophage to clear infections and terminate inflammation is attributed to the airway milieu in COPD but the mechanisms are not completely understood. Neutrophil elastase (NE),present in the COPD airway, may subvert macrophage function from protective to pro-inflammatory. Rationale: We demonstrate that NE is taken up by macrophages and targets the cytoplasm and nucleus, and NE exerts intracellular protease activity. NE degrades or modifies epigenetic regulators resulting in release of potent pro-inflammatory proteins: cytokines and High Mobility Group Box 1 (HMGB1), and release of macrophage extracellular traps (METs). Extracellular traps are DNA strands decorated with chromatin binding proteins, myeloperoxidase and NE; they trap and kill bacteria but they are also highly pro-inflammatory. Airway extracellular traps are associated with worse COPD lung disease.