Neutrophil Elastase Reprograms Macrophage Function in Chronic Obstructive Pulmonary Disease

Neutrophil elastase (NE) impairs phagocytic function. NE is taken up by human blood monocyte derived macrophages (hBMDM) and retains proteolytic activity in the macrophages, leading to cleaving of multiple targets. We discovered that NE clips Histone H3 in hBMDM resulting in chromatin decondensation and release of Macrophage Extracellular Traps (METs). We also discovered that NE cleaves histone deacetylases and sirtuin 1 resulting in unopposed acetyltransferase activity that causes translocation of a major alarmin, High Mobility Group Box 1 (HMGB1) from the nucleus to the cytosol. We have published three papers related to this project and have three additional papers in revision or in preparation about this work this year. We are completing analysis of hBMDM cell lysates from control subjects to determine whether NE increases acetyllysine modifications of Histone H3 or alters other cellular proteins critical for chromatin structure as part of the mechanism of increased inflammation and NE-activated METs release.