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 reactiveoxygen species (ROS) are involved in this process. However, the source of mitochondrial ROS and their speci fic role in NLRP3triggering are unclear. Here, we show that H2O2 produced by the mitochondrial enzyme monoamine oxidase B (MAO-B) plays anonredundant 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-1 β secretion, and MAO-Bdeficient mice showed an impaired response to LPS-mediated endotoxemia. Our findings identify MAO-B as a speci fic producer of mitochondrial ROS fueling the NLRP3 inflammasome, thereby providing a basis for repurposing MAOB inhibitors to treat inflammasome-mediated pathologies.
Targeting monoamine oxidase to dampen NLRP3 inflammasome activation in inflammation
Castegna, AlessandraMembro del Collaboration Group
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2020-01-01
Abstract
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 reactiveoxygen species (ROS) are involved in this process. However, the source of mitochondrial ROS and their speci fic role in NLRP3triggering are unclear. Here, we show that H2O2 produced by the mitochondrial enzyme monoamine oxidase B (MAO-B) plays anonredundant 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-1 β secretion, and MAO-Bdeficient mice showed an impaired response to LPS-mediated endotoxemia. Our findings identify MAO-B as a speci fic producer of mitochondrial ROS fueling the NLRP3 inflammasome, thereby providing a basis for repurposing MAOB inhibitors to treat inflammasome-mediated pathologies.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
