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

Abstract

The NLRP3 inflammasome, an intracellular multi-protein complex controlling the maturation of cytokine interleukin-1β, plays an important role in lipopolysaccharide (LPS)-induced inflammatory cascades. Recently, the production of mitochondrial reactive oxygen species (mtROS) in macrophages stimulated with LPS has been suggested to act as a trigger during the process of NLRP3 inflammasome activation that can be blocked by some mitochondria-targeted antioxidants. Known as a ROS scavenger, molecular hydrogen (H2) has been shown to possess therapeutic benefit on LPS-induced inflammatory damage in many animal experiments. Due to the unique molecular structure, H2 can easily target the mitochondria, suggesting that H2 is a potential antagonist of mtROS-dependent NLRP3 inflammasome activation. Here we have showed that, in mouse macrophages, H2 exhibited substantial inhibitory activity against LPS-initiated NLRP3 inflammasome activation by scavenging mtROS. Moreover, the elimination of mtROS by H2 resultantly inhibited mtROS-mediated NLRP3 deubiquitination, a non-transcriptional priming signal of NLRP3 in response to the stimulation of LPS. Additionally, the removal of mtROS by H2 reduced the generation of oxidized mitochondrial DNA and consequently decreased its binding to NLRP3, thereby inhibiting the NLRP3 inflammasome activation. Our findings have, for the first time, revealed the novel mechanism underlying the inhibitory effect of molecular hydrogen on LPS-caused NLRP3 inflammasome activation, highlighting the promising application of this new antioxidant in the treatment of LPS-associated inflammatory pathological damage.

Molecular hydrogen regulates PTEN‐AKT‐mTOR signaling via ROS to alleviate peritoneal dialysis‐related peritoneal fibrosis

“…23 And it has been reported that hydrogen can regulate ROS activation in macrophages. 24 Our research shows that molecular hydrogen significantly attenuated high glucose-induced mitochondrial membrane destruction in peritoneal MCs and reduced intracellular ROS production, consistent with the findings of studies on hydrogen effects on cerebral ischemia-reperfusion injury. 25 The production of ROS in peritoneal MCs and during epithelial-mesenchymal transition of peritoneal MCs have been important targets for prevention and treatment of peritoneal fibrosis.…”

“…High glucose peritoneal dialysate induces ROS production in peritoneal MCs, which promotes macrophage polarization to aggravate peritoneal mesothelial injury . And it has been reported that hydrogen can regulate ROS activation in macrophages . Our research shows that molecular hydrogen significantly attenuated high glucose‐induced mitochondrial membrane destruction in peritoneal MCs and reduced intracellular ROS production, consistent with the findings of studies on hydrogen effects on cerebral ischemia‐reperfusion injury …”

Dexmedetomidine Alleviates Hyperoxia-Induced Acute Lung Injury via Inhibiting NLRP3 Inflammasome Activation

“…Previous studies showed that stimulation by LPS plus ATP could trigger the activation of NLRP3 inflammasome in RAW264.7 cells [38, 39]. Here, we observed that exposure to hyperoxia could result in NLRP3 inflammasome activation in RAW264.7 cells, which was consistent with the previous studies.…”

Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD

“…Inflammasome independent pathways are activated following the induction of metabolic stress through fatty-acid induced ETC uncoupling (Freigang et al, 2013). This alludes to the existence of other mechanisms for inducing inflammation following altered mitochondrial function that do not necessarily involve pathogens or oxidative stress (Ren et al, 2016). In macrophages mitophagy protects against inflammation which can limit tissue repair by reducing damaged mitochondrial signaling from the Nlrp3- inflammasome (Zhong et al, 2016).…”