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

Abstract

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.

• Authors: Chih-Yu Hsieh, Lan-Hui Li, Yulin Lam, Zhanxiong Fang, Chin Heng Gan, Yerra Koteswara Rao, Hsiao-Wen Chiu, Wei-Ting Wong, Tz-Chuen Ju, Fang-Hsin Chen, Oleg V Chernikov, May-Lan Liu, Chung-Hua Hsu, Kuo-Feng Hua
• Journal: Cells (Cells) Vol. 9 Issue 2 (01 23 2020) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 31979265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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