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Hyperammonemia induces microglial NLRP3 inflammasome activation via mitochondrial oxidative stress in hepatic encephalopathy

 So Yeong Cheon  ;  Min-Yu Kim  ;  Jeongmin Kim  ;  Eun Jung Kim  ;  Eun Hee Kam  ;  Inja Cho  ;  Bon-Nyeo Koo  ;  So Yeon Kim 
 BIOMEDICAL JOURNAL, Vol.46(5) : 100593, 2023-10 
Journal Title
Issue Date
Bile duct ligation ; Hepatic encephalopathy ; Hyperammonemia ; Microglia ; NLRP3 inflammasome ; Reactive oxygen species
Background: The role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the pathogenesis of hepatic encephalopathy (HE) is unclear. Mitochondrial reactive oxygen species (mtROS) is a signal for NLRP3 inflammasome activation. Therefore, we aimed to determine whether mtROS-dependent NLRP3 inflammasome activation is involved in HE, using in vivo and in vitro models.

Methods: Bile duct ligation (BDL) in C57/BL6 mice was used as an in vivo HE model. NLRP3 activation was assessed in the hippocampus. Immunofluorescence staining was performed to determine the cellular source of NLRP3 in the hippocampal tissue. For the in vitro experiment, BV-2 microglial cells were primed with lipopolysaccharide (LPS), followed by ammonia treatment. NLRP3 activation and mitochondrial dysfunction were measured. Mito-TEMPO was used to suppress mtROS production.

Results: BDL mice showed cognitive impairment with hyperammonemia. Both the priming and activation steps of NLRP3 inflammasome activation were processed in the hippocampus of BDL mice. Moreover, intracellular ROS levels increased in the hippocampus, and NLRP3 was mainly expressed in the microglia of the hippocampus. In LPS-primed BV-2 cells, ammonia treatment induced NLRP3 inflammasome activation and pyroptosis, with elevation of mtROS and altered mitochondrial membrane potential. Pretreatment with Mito-TEMPO suppressed mtROS production and the subsequent NLRP3 inflammasome activation and pyroptosis under LPS and ammonia treatment in BV-2 cells.

Conclusions: Hyperammonemia in HE may be involved in mtROS overproduction and subsequent NLRP3 inflammasome activation. Further studies using NLRP3-specific inhibitor or NLRP3 knockout mice are needed to elucidate the important role of NLRP3 inflammasome in HE development.
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1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
Yonsei Authors
Koo, Bon-Nyeo(구본녀) ORCID logo https://orcid.org/0000-0002-3189-1673
Kim, Min-Yu(김민유)
Kim, So Yeon(김소연) ORCID logo https://orcid.org/0000-0001-5352-157X
Kim, Eun Jung(김은정) ORCID logo https://orcid.org/0000-0002-5693-1336
Kim, Jeongmin(김정민) ORCID logo https://orcid.org/0000-0002-0468-8012
Cho, Inja(조인자) ORCID logo https://orcid.org/0000-0001-5332-9115
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