Synthetic 4-Hydroxy Auxarconjugatin B, a Novel Autophagy Inducer, Attenuates Gouty Inflammation by Inhibiting the NLRP3 Inflammasome

Cells. 2020 Jan 23;9(2):279. doi: 10.3390/cells9020279.


Gouty arthritis results from the generation of uric acid crystals within the joints. These uric acid crystals activate the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, which is involved in chronic inflammatory diseases, including gouty arthritis. This study identified the polyenylpyrrole derivative 4-hydroxy auxarconjugatin B (4-HAB), a novel autophagy inducer, which attenuated uric acid crystals-mediated activation of the NLRP3 inflammasome in vitro and in vivo. 4-HAB dose-dependently reduced the release of interleukin (IL)-1β, IL-18, active caspase-1 and apoptosis-associated speck-like protein (ASC) in uric acid crystals-activated macrophages. In a mechanistic study, 4-HAB was shown to inhibit uric acid crystals-induced mitochondrial damage, lysosomal rupture and ASC oligomerization. Additionally, 4-HAB inhibited the NLRP3 inflammasome through Sirt1-dependent autophagy induction. Furthermore, the anti-inflammatory properties of 4-HAB were confirmed in a mouse model of uric acid crystals-mediated peritonitis by the reduced levels of neutrophil influx, IL-1β, active caspase-1, IL-6 and MCP-1 in lavage fluids. In conclusion, 4-HAB attenuates gouty inflammation, in part by attenuating activation of the NLRP3 inflammasome through the Sirt1/autophagy induction pathway.

Keywords: 4-hydroxy auxarconjugatin B; NLRP3 inflammasome; autophagy; gouty inflammation; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Gouty / complications
  • Arthritis, Gouty / pathology*
  • Autophagy / drug effects*
  • CARD Signaling Adaptor Proteins / metabolism
  • Cell Line
  • Disease Models, Animal
  • Humans
  • Inflammasomes / metabolism*
  • Inflammation / complications
  • Inflammation / pathology*
  • Lipopolysaccharides
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / pathology
  • Models, Biological
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Organelle Biogenesis
  • Protein Multimerization / drug effects
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Sirtuin 1 / metabolism


  • CARD Signaling Adaptor Proteins
  • Inflammasomes
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pycard protein, mouse
  • Pyrroles
  • Sirtuin 1