Molecular hydrogen inhibits lipopolysaccharide-triggered NLRP3 inflammasome activation in macrophages by targeting the mitochondrial reactive oxygen species.

Abstract

In mouse macrophages stimulated with lipopolysaccharide (LPS), molecular hydrogen (H2) was found to substantially suppress NLRP3 inflammasome activation, a multi-protein complex governing interleukin-1β maturation. H2 achieved this by scavenging mitochondrial reactive oxygen species (mtROS). Two distinct downstream mechanisms were identified: first, mtROS elimination by H2 blocked NLRP3 deubiquitination, a non-transcriptional priming event triggered by LPS; second, H2 reduced the generation of oxidized mitochondrial DNA, thereby diminishing its interaction with NLRP3 and further attenuating inflammasome assembly. These findings provide the first mechanistic account of how H2 interferes with LPS-driven NLRP3 inflammasome signaling in macrophages, centered on mitochondria-targeted antioxidant activity.

Mechanism

H2 scavenges mitochondrial ROS, thereby blocking NLRP3 deubiquitination and reducing oxidized mitochondrial DNA production; both effects converge to inhibit NLRP3 inflammasome assembly and IL-1β maturation in LPS-stimulated macrophages.