NOX2 deficiency promotes GSDME-related pyroptosis by reducing AMPK activation in neutrophils

Nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2) is an effector molecule expressed predominantly in neutrophils. Its deficiency is present in immune disorders, including systemic lupus erythematosus, chronic granulomatous disease, and rheumatoid arthritis. Recent reports indicated that NOX2 regulates autoimmunity and programmed cell death. However, the exact mechanism is unclear. In this study, we explored the effect of NOX2 on neutrophil apoptosis. We demonstrated that NOX2 deficiency caused neutrophil pyroptosis. Mechanistically, the NOX2 inhibitor GSK2795039 application or knockdown of NOX2 components resulted in increased mitochondrial ROS, inhibition of AMP-activated protein kinase (AMPK), and activation of Gasdermin E. AMPK activators, metformin and epigallocatechin gallate, inhibited deficient NOX2-induced pyroptosis. Together, these findings illustrate the involvement of NOX2 in regulating neutrophil death and emphasize its importance in autoimmunity.