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Updated: Jun 22, 2025

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
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Published on: May 22, 2014

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UK5099 Inhibits the NLRP3 Inflammasome Independently of its Long-Established Target Mitochondrial Pyruvate Carrier

Linyu Ran1,2, Miao Chen3, Jihui Ye1,2

  • 1Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200120, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 1, 2024
PubMed

Insights

UK5099, an inhibitor of mitochondrial pyruvate carrier (MPC), potently inhibits the NLRP3 inflammasome, independent of MPC. This discovery offers new therapeutic avenues for NLRP3-driven diseases and impacts immunometabolism research.

Area of Science:

  • Immunology
  • Molecular Biology
  • Drug Discovery

Background:

  • The NLRP3 inflammasome is a key target for treating inflammatory diseases.
  • UK5099, an established mitochondrial pyruvate carrier (MPC) inhibitor, has shown anti-inflammatory effects independent of MPC.
  • The precise mechanisms of UK5099's anti-inflammatory action were previously unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying UK5099's anti-inflammatory effects.
  • To determine if UK5099 targets the NLRP3 inflammasome.
  • To explore the therapeutic potential of UK5099 in NLRP3-mediated inflammatory conditions.

Main Methods:

  • Assessed UK5099's effect on NLRP3 inflammasome activation in mouse and human macrophages.
  • Utilized macrophages lacking MPC expression to confirm MPC-independent activity.
  • Investigated the interaction between mitochondria and NLRP3 upon UK5099 treatment.
  • Evaluated the in vivo efficacy of UK5099 in an endotoxemia mouse model.
  • Performed structure-activity relationship studies on UK5099.

Main Results:

  • UK5099 demonstrated potent and selective inhibition of NLRP3 inflammasome activation, without affecting NLRC4 or AIM2.
  • The inhibitory effect of UK5099 on NLRP3 was confirmed to be independent of MPC expression.
  • UK5099 was found to disrupt the interaction between mitochondria and NLRP3, preventing inflammasome assembly.
  • A single dose of UK5099 significantly reduced IL-1β production in vivo.
  • Structural analysis indicated that the inhibitory activity of UK5099 is not dependent on its activated double bond.

Conclusions:

  • UK5099 is a novel and potent inhibitor of the NLRP3 inflammasome, acting via disruption of mitochondria-NLRP3 interaction.
  • This finding identifies UK5099 as a potential therapeutic agent for NLRP3-driven inflammatory diseases.
  • The MPC-independent NLRP3 inhibitory activity of UK5099 necessitates re-evaluation of its use in immunometabolism studies.
Keywords:
NLRP3UK5099macrophagemetabolismmitochondrial pyruvate carrier

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