Lipid chlorination mobilizes Neutrophil Elastase to initiate NETosis

Abstract

Neutrophils are the first cells recruited to sites of infection, where they contain and kill pathogens through phagocytosis, degranulation, and the release of neutrophil extracellular traps (NETs) - web-like structures of decondensed chromatin that trap and destroy microbes. NET formation is essential for host defense, but when dysregulated it also contributes to disease, including sepsis, autoimmunity, and thrombosis. A central step in NET release is the translocation of neutrophil elastase (NE) from azurophilic granules to the nucleus, yet how NE crosses the granule membrane has remained unresolved. Using neutrophils and granules from healthy donors and from patients deficient in NADPH oxidase or myeloperoxidase (MPO), we show that MPO-derived hypochlorous acid chlorinates plasmalogens abundant in the granule membrane, generating 2-chlorofatty acids that permeabilize the granule and release NE into the cytosol. This reaction requires chloride, occurs within transient intracellular oxidant-rich compartments, and is both necessary and sufficient to trigger NE mobilization and NET formation. These findings identify lipid chlorination as the chemical link between the neutrophil oxidative burst and the execution of NETosis.