2. Academic Validation
  3. Chaetocin attenuates gout in mice through inhibiting HIF-1α and NLRP3 inflammasome-dependent IL-1β secretion in macrophages

Chaetocin attenuates gout in mice through inhibiting HIF-1α and NLRP3 inflammasome-dependent IL-1β secretion in macrophages

  • Arch Biochem Biophys. 2019 Jul 30;670:94-103. doi: 10.1016/j.abb.2019.06.010.
Mian Wu 1,  Mingliang Zhang 1,  Yiwen Ma 1,  Fengjing Liu 1,  Si Chen 1,  Junxi Lu 1,  Haibing Chen 2
Affiliations

Affiliations

  • 1 Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 2 Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China. Electronic address: [email protected].
PMID: 31255694 DOI: 10.1016/j.abb.2019.06.010
Abstract

Chaetocin is a Fungal metabolite that possesses a potential anti-inflammatory activity. Acute gout is a self-limiting inflammatory response to monosodium urate (MSU) crystals. However, the effect of cheatocin on gout has not been elucidated. In the study, we found that chaetocin could decrease MSU induced IL-1β secretion in bone marrow derived macrophages by several mechanisms, including inhibiting the activation of NLRP3 inflammasome. Chaetocin negatively regulated apoptosis-associated speck-like protein with a CARD domain oligomerization, and Caspase-1 processing, key events during inflammasome activation. Furthermore, chaetocin restrain expressions of Hypoxia-inducible factor-1α and Hexokinase 2, mediators of glycolysis, which necessary for synthesis of pro-IL-1β during inflammasome priming. In vivo, chaetocin ameliorate MSU-induced arthritis, which showed as reduced local swelling and inflammatory cell infiltration. In MSU-induced peritonitis model, the peritoneal macrophages of chaetocin-pretreated mice showed significantly decreased mRNA levels of HIF-1α and NLRP3 related genes. These findings suggested that chaetocin has a potent anti-inflammatory effect against gout. More importantly, it is proposed that the inhibiting of glycolysis pathway would be a new avenue for the treatment of gout flare and other IL-1β related diseases.

Keywords

Chaetocin; Gout; HIF-1α; IL-1β; Macrophage; NLRP3.

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