Targeting monoamine oxidase to dampen NLRP3 inflammasome activation in inflammation

Inflammasomes represent protective weapons against pathogens and cellular damage, although their uncontrolled activation drives the progression of inflammatory, metabolic, and neurodegenerative disorders. Several signals activate the NLRP3 inflammasome, and a few studies have reported that mitochondrial reactive oxygen species (ROS) are involved in this process. However, the source of mitochondrial ROS and their specific role in NLRP3 triggering are unclear. Here, we show that H2O2 produced by the mitochondrial enzyme monoamine oxidase B (MAO-B) plays a nonredundant role in sustaining NLRP3 inflammasome activation. Mechanistically, MAO-B-dependent ROS formation caused mitochondrial dysfunction and NF-κB induction, resulting in NLRP3 and pro-IL-1β overexpression. Both in vitro and in vivo, MAO-B inhibition by rasagiline prevented IL-1β secretion, and MAO-B-deficient mice showed an impaired response to LPS-mediated endotoxemia. Our findings identify MAO-B as a specific producer of mitochondrial ROS fueling the NLRP3 inflammasome, thereby providing a basis for repurposing MAOB inhibitors to treat inflammasome-mediated pathologies.