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合成 4-羟基 Auxarconjugatin B，一种新型自噬诱导剂，通过抑制 NLRP3 炎性体来减轻痛风性炎症。

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

机构信息

Department of Biotechnology and Animal Science, National Ilan University, Ilan 260, Taiwan.

Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei 10844, Taiwan.

出版信息

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

DOI:10.3390/cells9020279
PMID:31979265
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7072356/
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.

摘要

痛风性关节炎是由关节内尿酸晶体的生成引起的。这些尿酸晶体激活了包含 NACHT、LRR 和 PYD 结构域的蛋白 3（NLRP3）炎症小体，该炎症小体参与慢性炎症性疾病，包括痛风性关节炎。本研究鉴定了聚烯基吡咯衍生物 4-羟基 auxarconjugatin B（4-HAB），一种新型自噬诱导剂，可减轻尿酸晶体介导的 NLRP3 炎症小体在体外和体内的激活。4-HAB 呈剂量依赖性降低尿酸晶体激活的巨噬细胞中白细胞介素（IL）-1β、IL-18、活性半胱天冬酶-1 和凋亡相关斑点样蛋白（ASC）的释放。在机制研究中，4-HAB 被证明可抑制尿酸晶体诱导的线粒体损伤、溶酶体破裂和 ASC 寡聚化。此外，4-HAB 通过 Sirt1 依赖性自噬诱导抑制 NLRP3 炎症小体。此外，通过降低灌洗液中中性粒细胞浸润、IL-1β、活性半胱天冬酶-1、IL-6 和 MCP-1 的水平，在尿酸晶体介导的腹膜炎小鼠模型中证实了 4-HAB 的抗炎特性。总之，4-HAB 通过 Sirt1/自噬诱导途径减轻痛风性炎症，部分是通过减轻 NLRP3 炎症小体的激活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/fe861ee84bfc/cells-09-00279-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/b40b922fc1e9/cells-09-00279-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/859e6160f77c/cells-09-00279-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/bed98211d149/cells-09-00279-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/e846075770a3/cells-09-00279-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/53fd898e3000/cells-09-00279-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/a6651053174d/cells-09-00279-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/fe861ee84bfc/cells-09-00279-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/b40b922fc1e9/cells-09-00279-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/859e6160f77c/cells-09-00279-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/bed98211d149/cells-09-00279-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/e846075770a3/cells-09-00279-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/53fd898e3000/cells-09-00279-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/a6651053174d/cells-09-00279-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d675/7072356/fe861ee84bfc/cells-09-00279-g007.jpg

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