Obovatol inhibits NLRP3, AIM2, and non-canonical inflammasome activation

Phytomedicine. 2019 Oct:63:153019. doi: 10.1016/j.phymed.2019.153019. Epub 2019 Jul 4.

Abstract

Background: Obovatol, a biphenolic chemical originating from Magnolia obovata, has been utilized as a traditional medicine for the treatment of inflammatory diseases. Inflammasome induces maturation of inflammatory cytokines in response to intracellular danger signals, and its dysregulation induces inflammatory diseases.

Purpose: The effect of obovatol on inflammasome activation has not been reported, although its anti-inflammatory properties have been studied.

Study design/methods: Obovatol was treated to macrophages with inflammasome triggers, and secretions of interleukin (IL)-1β, IL-18, and caspase-1 were measured as readouts of inflammasome activation. In addition, Asc pyroptosome formation, caspase-1 activity, and mitochondrial reactive oxygen species (ROS) production were analyzed in mechanical studies. Anti-inflammasome properties of obovatol were confirmed in an animal model.

Results: Obovatol inhibited NLRP3, AIM2, and non-canonical inflammasomes through inhibition of Asc pyroptosome formation and mitochondrial ROS generation. In addition, obovatol disrupted the priming step of inflammasome activation and inhibited transcription of inflammatory cytokines. In mice, obovatol attenuated serum IL-1β elevation in response to monosodium urate crystals.

Conclusion: Obovatol is suggested as an inhibitor of NLRP3, AIM2, and non-canonical inflammasomes.

Keywords: Inflammasome; Interleukin-1beta; Macrophages; Obovatol.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology*
  • Caspase 1 / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Inflammasomes / drug effects*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Peritonitis / drug therapy
  • Phenyl Ethers / chemistry
  • Phenyl Ethers / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Uric Acid / pharmacology

Substances

  • AIM2 protein, human
  • Aim2 protein, mouse
  • Anti-Inflammatory Agents, Non-Steroidal
  • Biphenyl Compounds
  • Cytokines
  • DNA-Binding Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Phenyl Ethers
  • Reactive Oxygen Species
  • Uric Acid
  • obovatol
  • Casp1 protein, mouse
  • Caspase 1