Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps

TLDR

Neutrophils release extracellular traps composed of decondensed chromatin to capture pathogens, and while reactive oxygen species initiate this process, the downstream molecular steps remain unclear. Upon activation, neutrophil elastase exits azurophilic granules, enters the nucleus, partially degrades histones to drive chromatin decondensation, and myeloperoxidase cooperates with elastase in a non‑enzymatic manner to further promote this decondensation. Neutrophil elastase knockout mice fail to generate NETs during Klebsiella pneumoniae lung infection, implicating elastase in host defense, and the study reveals that serine proteases and granular proteins regulate chromatin density while an oxidative burst triggers selective release of these proteins into the cytoplasm through an as‑yet‑unknown pathway.

Abstract

Neutrophils release decondensed chromatin termed neutrophil extracellular traps (NETs) to trap and kill pathogens extracellularly. Reactive oxygen species are required to initiate NET formation but the downstream molecular mechanism is unknown. We show that upon activation, neutrophil elastase (NE) escapes from azurophilic granules and translocates to the nucleus, where it partially degrades specific histones, promoting chromatin decondensation. Subsequently, myeloperoxidase synergizes with NE in driving chromatin decondensation independent of its enzymatic activity. Accordingly, NE knockout mice do not form NETs in a pulmonary model of Klebsiella pneumoniae infection, which suggests that this defect may contribute to the immune deficiency of these mice. This mechanism provides for a novel function for serine proteases and highly charged granular proteins in the regulation of chromatin density, and reveals that the oxidative burst induces a selective release of granular proteins into the cytoplasm through an unknown mechanism.