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Cells. 2020 Jan 23;9(2). pii: E279. doi: 10.3390/cells9020279.

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

Author information

1
Department of Biotechnology and Animal Science, National Ilan University, Ilan 260, Taiwan.
2
Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei 10844, Taiwan.
3
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11483, Taiwan.
4
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
5
Department of Animal Science and Biotechnology, Tunghai University, Taichung 407, Taiwan.
6
Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan 33302, Taiwan.
7
G.B. Elyakov Pacific Institute of Bioorganic Chemistry FEB RAS, Vladivostok 690022, Russia.
8
Department of Nutritional Science, Toko University, Chiayi 61363, Taiwan.
9
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
10
Department of Chinese Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei 10844, Taiwan.
11
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan.

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.

KEYWORDS:

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

PMID:
31979265
DOI:
10.3390/cells9020279
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