SOD1 controls neutrophil oxidative burst and microbial killing

Neutrophils are immune cells specialized in producing large amounts of reactive oxygen species (ROS) to kill microbes. However, the mechanisms by which these cells regulate the balance of different ROS species and mitigate oxidative stress remain unclear. Here, we demonstrate that superoxide dismutase 1 (SOD1) plays a crucial role in ROS formation and antimicrobial activity in neutrophils. Our findings reveal that SOD1 modulates the ratio of superoxide (O ₂ ^- ) to hydrogen peroxide (H ₂ O ₂ ) during the ROS burst, thereby supporting myeloperoxidase (MPO) enzymatic activity. By employing biochemical, cell biological, and genetic approaches, we show that SOD1 is crucial for ROS formation during NETosis and microbial infections, as it reduces oxidative stress and enables complete neutrophil activation. Impairment of SOD1 activity increases cysteine oxidation and lipid peroxidation. Neutrophils isolated from a patient with a SOD1 mutation exhibit decreased ROS production and impaired neutrophil extracellular trap (NET) formation. Our findings suggest that SOD1 is a novel regulatory factor in the oxidative burst that enables the full immunological response of neutrophils.