Identification of ethyl pyruvate as a NLRP3 inflammasome inhibitor that preserves mitochondrial integrity

Autor: Fang Liang, Sangeeta S. Chavan, Kevin J. Tracey, Xiangyu Wang, Jianhua Li, Kevin Kwan, Yiting Tang, Sujun Li, Youzhou Tang, Ulf Andersson, Ben Lu, Haichao Wang, Huan Yang
Rok vydání: 2018
Předmět:
0301 basic medicine
Mitochondrial DNA
Nigericin
Inflammasomes
THP-1 Cells
Interleukin-1beta
chemical and pharmacologic phenomena
Inflammation
Mitochondrion
HMGB1
Ethyl pyruvate
lcsh:Biochemistry
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
NLR Family
Pyrin Domain-Containing 3 Protein
Genetics
medicine
Animals
Humans
The NLRP3 inflammasomes
lcsh:QD415-436
Pyruvates
Molecular Biology
Genetics (clinical)
chemistry.chemical_classification
Reactive oxygen species
Mitochondrial damage
biology
Tumor Necrosis Factor-alpha
Macrophages
lcsh:RM1-950
Inflammasome
Mitochondria
Cell biology
Mice
Inbred C57BL
Cytosol
lcsh:Therapeutics. Pharmacology
030104 developmental biology
chemistry
biology.protein
Molecular Medicine
medicine.symptom
Research Article
030215 immunology
medicine.drug
Zdroj: Molecular Medicine
Molecular Medicine, Vol 24, Iss 1, Pp 1-11 (2018)
ISSN: 1528-3658
1076-1551
Popis: Background The NLRP3 inflammasome, a cytosolic complex that mediates the maturation of IL-1β and IL-18 as well as the release of high mobility group box 1 (HMGB1), contributes to the lethality of endotoxic shock. Ethyl pyruvate (EP) was previously shown to inhibit HMGB1 release and promote survival during endotoxemia and experimental sepsis. However, the underlying protective mechanism remains elusive. Result EP dose-dependently inhibited the ATP-, nigericin-, alum-, and silica-induced caspase-1 activation and HMGB1 release in mouse macrophages. EP failed to inhibit DNA transfection- or Salmonella Typhimurium-induced caspase-1 activation and HMGB1 release. Mechanistically, EP significantly attenuated mitochondrial damage and cytoplasmic translocation of mitochondrial DNA, a known NLRP3 ligand, without influencing the potassium efflux, the lysosomal rupture or the production of mitochondrial reactive oxygen species (mtROS). Conclusion Ethyl pyruvate acts as a novel NLRP3 inflammasome inhibitor that preserves the integrity of mitochondria during inflammation.
Databáze: OpenAIRE
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