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

被引：34

作者：

Hsieh, Chih-Yu ^{[1
]}

Li, Lan-Hui ^{[2
,3
]}

Lam, Yulin ^{[4
]}

Fang, Zhanxiong ^{[4
]}

Gan, Chin Heng ^{[4
]}

Rao, Yerra Koteswara ^{[1
]}

Chiu, Hsiao-Wen ^{[1
]}

Wong, Wei-Ting ^{[1
]}

Ju, Tz-Chuen ^{[5
]}

Chen, Fang-Hsin ^{[6
]}

Chernikov, Oleg V. ^{[7
]}

Liu, May-Lan ^{[8
]}

Hsu, Chung-Hua ^{[9
,10
]}

Hua, Kuo-Feng ^{[1
,3
,11
]}

机构：

[1] Natl Ilan Univ, Dept Biotechnol & Anim Sci, Ilan 260, Taiwan

[2] Taipei City Hosp, Chinese Med & Kunming Branch, Dept Lab Med, Taipei 10844, Taiwan

[3] Triserv Gen Hosp, Dept Pathol, Natl Def Med Ctr, Taipei 11483, Taiwan

[4] Natl Univ Singapore, Dept Chem, 3 Sci Dr 3, Singapore 117543, Singapore

[5] Tunghai Univ, Dept Anim Sci & Biotechnol, Taichung 40704, Taiwan

[6] Chang Gung Univ, Dept Med Imaging & Radiol Sci, Taoyuan 33302, Taiwan

[7] RAS, FEB, GB Elyakov Pacific Inst Bioorgan Chem, Vladivostok 690022, Russia

[8] Toko Univ, Dept Nutr Sci, Chiayi 61363, Taiwan

[9] Natl Yang Ming Univ, Inst Tradit Med, Sch Med, Taipei 11221, Taiwan

[10] Taipei City Hosp, Chinese Med & Kunming Branch, Dept Chinese Med, Taipei 10844, Taiwan

[11] China Med Univ, China Med Univ Hosp, Dept Med Res, Taichung 40402, Taiwan

来源：

CELLS | 2020年 / 9卷 / 02期

关键词：

4-hydroxy auxarconjugatin B; NLRP3; inflammasome; mitochondria; autophagy; gouty inflammation; SIRT1; MECHANISMS; CASPASES; SIGNAL;

D O I：

10.3390/cells9020279

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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)-1 beta, 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-1 beta, 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.

引用

页数：17

共 37 条

[1]

The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response [J].