Elucidating the Role of Histone Acetylation in Regulating Neutrophil Extracellular Trap Formation

Neutrophils undergo a unique form of cell death to generate neutrophil extracellular traps (NETs). However, the importance of histone acetylation (e.g., acetylated histone H4, AcH4) in NET formation (NETosis) has not been established. Belinostat and panobinostat are pan histone deacetylase inhibitors (HDACis) and are widely used in clinical and laboratory applications. However, the relevance of these HDACis in altering neutrophil death is yet unknown. We considered that HDACis-induced AcH4 would dose-dependently alter neutrophil cell death between NETosis and apoptosis. The presence of HDACis (≤0.25 µM Belinostat; ≤0.04 µM panobinostat) significantly induced AcH4 and NETosis without promoting reactive oxygen species (ROS) production. Increasing concentrations of HDACis (>1 µM belinostat; >0.2 µM panobinostat) further induced H4 acetylation, NOX-derived ROS production, and significantly inhibited NETosis and induced apoptosis. However, in the presence of NETosis-inducing stimuli, higher concentrations of HDACis limited both NETosis and Apoptosis. Therefore, HDACis differentially regulate both NETosis and neutrophil apoptosis.M.Sc