Neutrophil Elastase Reprograms Macrophage Function in Chronic Obstructive Pulmonary Disease

The central hypothesis of this proposal is that extracellular NE is taken up by macrophages and accumulates in both cytoplasmic organelles and the nucleus. NE activity degrades histone deacetylase 2 (HDAC2) and possibly other HDACS and Sirtuins resulting in increased acetylation of several targets including histone H3, High Mobility Group Box 1 (HMGB1) and nuclear factor kappa B (NFkB) p65, resulting in increased cytokine transcription and release of HMGB1 (AIM 1). Nuclear NE cleaves histone H3 and increases H3 citrulline resulting in chromatin decondensation and release of vital nuclear METs (AIM 2).