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Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy?mediated NLRP3 inflammasome inactivation in sepsis.

ABSTRACT: Sepsis is a highly heterogeneous syndrome that is caused by a dysregulated host response to infection. The disproportionate inflammatory response to invasive infection is a triggering event inducing sepsis. The activation of in?ammasomes in sepsis can amplify in?ammatory responses. It has been reported that damaged mitochondria contribute to NACHT, LRR and PYD domains?containing protein 3 (NLRP3) inflammasome?related sepsis. Our previous study revealed that hydrogen (H2) exerts anti?inflammatory effects in sepsis but the detailed mechanism remains to be elucidated. In the present study, septic mice induced by cecal ligation and puncture (CLP) and macrophages induced by lipopolysaccharide (LPS) were used as models of sepsis in vivo and in vitro, respectively. An inducer and inhibitor of autophagy and the NLRP3 inflammasome were administered to investigate the detailed mechanism of action of H2 treatment in sepsis. The results demonstrated that LPS and ATP led to NLRP3 inflammasome pathway activation, excessive cytokine release, mitochondrial dysfunction and the activation of autophagy. CLP induced organ injury and NLRP3 pathway activation. H2 treatment ameliorated vital organ damage, the inflammatory response, mitochondrial dysfunction and NLRP3 pathway activation, and promoted autophagy in macrophages induced by LPS and in CLP mice. However, the inhibitor of autophagy and the inducer of NLRP3 reversed the protective effect of H2 against organ damage, the inflammatory response and mitochondrial dysfunction in vivo and in vitro. Collectively, the results demonstrated that H2 alleviated mitochondrial dysfunction and cytokine release via autophagy?mediated NLRP3 inflammasome inactivation.

SUBMITTER: Chen H

PROVIDER: S-EPMC6713420 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy‑mediated NLRP3 inflammasome inactivation in sepsis.

Chen Hongguang H Mao Xing X Meng Xiaoyin X Li Yuan Y Feng Jingcheng J Zhang Linlin L Zhang Yang Y Wang Yaoqi Y Yu Yonghao Y Xie Keliang K

International journal of molecular medicine 20190813 4

Sepsis is a highly heterogeneous syndrome that is caused by a dysregulated host response to infection. The disproportionate inflammatory response to invasive infection is a triggering event inducing sepsis. The activation of inﬂammasomes in sepsis can amplify inﬂammatory responses. It has been reported that damaged mitochondria contribute to NACHT, LRR and PYD domains‑containing protein 3 (NLRP3) inflammasome‑related sepsis. Our previous study revealed that hydrogen (H2) exerts anti‑inflammatory ...[more]

PMID: 31432098

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Project description:Aims/introductionAs a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevoflurane-induced neurotoxicity has attracted widespread attention in recent years. However, its mechanism has not been determined. This study aimed to observe the effects of sevoflurane on cognitive function and the changes in inflammatory indices and autophagy protein expression in the prefrontal cortex in aged rats.MethodBefore the experiment, D-galactose was diluted with normal saline into a liquid with a concentration of 125 mg/kg and injected subcutaneously into the neck and back of rats for 42 days to establish the aging rat model. Morris water maze experiments were performed, including positioning navigation (5 days) and space exploration (1 day). The POCD model was established by 3.2% sevoflurane inhalation. The rats were treated with or without MCC950, a potent and selective nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inhibitor, followed by autophagy agonists and autophagy inhibitors. The expression levels of inflammasome-related protein NLRP3 and autophagy-related proteins LC3B and P62 were detected to test the behavior of rats with a water maze.ResultsWe found that sevoflurane exposure affected learning and working memory ability in aged rats. We also observed microglia activation in the prefrontal cortex. NLRP3 protein expression was significantly upregulated after sevoflurane inhalation. NLRP3 inflammasome activation induced increased expression and mRNA expression of cleaved Caspase-1 and inflammatory cytokines IL-1β and IL-18, and increased secretion of peripheral proinflammatory cytokines. The inhibitor MCC950 was used to improve cognitive ability and inflammation in rats and inhibit the secretion of cytokines. In addition, we demonstrated that significant inhibition of autophagy (decreased LC3-II/I and increased P62) was accompanied by increased activation of NLRP3 inflammasomes and more severe neural cell damage. However, autophagy inhibitor rapamycin administration to activate autophagy resulted in the inhibition of NLRP3 inflammasomes, ultimately attenuating neuronal injury.ConclusionsThe activation of autophagy suppressed the formation of NLRP3 inflammasomes. It also alleviated cognitive impairment in aged rats.

Project description:Chronic muscle inflammation exacerbates the pathogenesis of Duchenne muscular dystrophy (DMD), which is characterized by progressive muscle degeneration and weakness. NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome plays a key role in the inflammatory process, and its abnormal activation leads to a variety of inflammatory or immune diseases. TRIM72 (MG53) is a protective myokine for tissue repair and regeneration. However, little is known about the potential impact of TRIM72 in the crosstalk between mitophagy and inflammatory process of DMD. Here, 10-week-old male mdx mice were injected intramuscularly with adeno-associated virus (AAV-TRIM72) to overexpress TRIM72 protein for 6 weeks. Then, skeletal muscle samples were collected, and relevant parameters were measured by histopathological analysis and molecular biology techniques. C2C12 cell line was transfected with lentivirus (LV-TRIM72) to overexpress or siRNA (si-TRIM72) to suppress the TRIM72 expression for the following experiment. Our data firstly showed that the TRIM72 expression was decreased in skeletal muscles of mdx mice. Then, we observed the increased NLRP3 inflammasome and impaired mitophagy in mdx mice compared with wild type mice. In mdx mice, administration of AAV-TRIM72 alleviated the accumulation of NLRP3 inflammasome and the consequent IL-18 and IL1β maturation by inducing autophagy, while this protective effect was reversed by chloroquine. Mitochondrial reactive oxygen species (mtROS), as a recognized activator for NLRP3 inflammasome, was attenuated by TRIM72 through the induction of mitophagy in C2C12 cells. Additionally, we proposed that the TRIM72 overexpression might promote mitophagy through both the early stage by PI3K-AKT pathway and the late stage by autolysosome fusion. In conclusion, the current study suggests that TRIM72 prevents DMD inflammation via decreasing NLRP3 inflammasomes and enhancing mitophagy. Collectively, our study provides insight into TRIM72 as a promising target for therapeutic intervention for DMD.

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Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy?mediated NLRP3 inflammasome inactivation in sepsis.

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Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy‑mediated NLRP3 inflammasome inactivation in sepsis.

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