Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice

doi:10.1038/s41401-023-01212-5

科研成果详情

题名	Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice
作者	Shao, Jing-Jing1,2; Li, Wei-Feng2; Sun, Jin-Feng 3,4; Zhuang, Zai-Shou 5; Min, Ju-Lian 1; Long, Xiao-Hong 2; Wu, Gao-Jun1; Xu, Hao-Wen2,3; Liang, Guang1,3
发表日期	2024-04
发表期刊	ACTA PHARMACOLOGICA SINICA 影响因子和分区
语种	英语
原始文献类型	Article ; Early Access ; Journal Article
关键词	inflammation NLRP3 inflammasome Britannin gouty arthritis acute lung injury systemic infection
其他关键词	OLT1177
摘要	Overactivation of the NLRP3 inflammasomes induces production of pro-inflammatory cytokines and drives pathological processes. Pharmacological inhibition of NLRP3 is an explicit strategy for the treatment of inflammatory diseases. Thus far no drug specifically targeting NLRP3 has been approved by the FDA for clinical use. This study was aimed to discover novel NLRP3 inhibitors that could suppress NLRP3-mediated pyroptosis. We screened 95 natural products from our in-house library for their inhibitory activity on IL-1 beta secretion in LPS + ATP-challenged BMDMs, found that Britannin exerted the most potent inhibitory effect with an IC50 value of 3.630 mu M. We showed that Britannin (1, 5, 10 mu M) dose-dependently inhibited secretion of the cleaved Caspase-1 (p20) and the mature IL-1 beta, and suppressed NLRP3-mediated pyroptosis in both murine and human macrophages. We demonstrated that Britannin specifically inhibited the activation step of NLRP3 inflammasome in BMDMs via interrupting the assembly step, especially the interaction between NLRP3 and NEK7. We revealed that Britannin directly bound to NLRP3 NACHT domain at Arg335 and Gly271. Moreover, Britannin suppressed NLRP3 activation in an ATPase-independent way, suggesting it as a lead compound for design and development of novel NLRP3 inhibitors. In mouse models of MSU-induced gouty arthritis and LPS-induced acute lung injury (ALI), administration of Britannin (20 mg/kg, i.p.) significantly alleviated NLRP3-mediated inflammation; the therapeutic effects of Britannin were dismissed by NLRP3 knockout. In conclusion, Britannin is an effective natural NLRP3 inhibitor and a potential lead compound for the development of drugs targeting NLRP3.
资助项目	National Natural Science Foundation of China [82360805]; Zhejiang Province Traditional Chinese Medicine Science and Technology Project [2024ZF056]; Zhejiang Provincial Key Scientific Project [2021C03041]
出版者	NATURE PUBL GROUP
ISSN	1671-4083
EISSN	1745-7254
卷号	45 期号:4 页码:803-814
DOI	10.1038/s41401-023-01212-5
页数	12
WOS类目	Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
WOS记录号	WOS:001135191700001
收录类别	SCIE ; PUBMED ; SCOPUS
在线发表日期	2024-01
URL	查看原文
PubMed ID	38172305
SCOPUSEID	2-s2.0-85181246915
通讯作者地址	[Liang, Guang]Department of Cardiology and Medical Research Center,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325035,China ; [Xu, Hao-Wen]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China
Scopus学科分类	Pharmacology;Pharmacology (medical)
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/209700
专题	附属第一医院药学院（分析测试中心）_生物有机与药物化学研究中心其他_附属苍南医院（苍南县人民医院）
通讯作者	Xu, Hao-Wen; Liang, Guang
作者单位	1.Department of Cardiology and Medical Research Center,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325035,China; 2.Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China; 3.School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou,311399,China; 4.Key Laboratory of Natural Medicines of the Changbai Mountain,Ministry of Education,School of Pharmaceutical Sciences,Yanbian University,Yanji,133002,China; 5.Affiliated Cangnan Hospital,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China
第一作者单位	附属第一医院; 第一临床医学院（信息与工程学院）、附属第一医院; 药学院（分析测试中心）; 生物有机与药物化学研究中心
通讯作者单位	附属第一医院; 第一临床医学院（信息与工程学院）、附属第一医院; 药学院（分析测试中心）; 生物有机与药物化学研究中心
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Shao, Jing-Jing,Li, Wei-Feng,Sun, Jin-Feng,et al. Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice[J]. ACTA PHARMACOLOGICA SINICA,2024,45(4):803-814.
APA	Shao, Jing-Jing., Li, Wei-Feng., Sun, Jin-Feng., Zhuang, Zai-Shou., Min, Ju-Lian., ... & Liang, Guang. (2024). Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice. ACTA PHARMACOLOGICA SINICA, 45(4), 803-814.
MLA	Shao, Jing-Jing,et al."Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice".ACTA PHARMACOLOGICA SINICA 45.4(2024):803-814.