1. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity.
- Author
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He H, Jiang H, Chen Y, Ye J, Wang A, Wang C, Liu Q, Liang G, Deng X, Jiang W, and Zhou R
- Subjects
- Animals, Anti-Inflammatory Agents isolation & purification, Arthritis, Gouty genetics, Arthritis, Gouty immunology, Arthritis, Gouty pathology, Blood Glucose metabolism, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 immunology, Diabetes Mellitus, Type 2 pathology, Disease Models, Animal, Diterpenes, Kaurane isolation & purification, Gene Expression Regulation, Humans, Inflammasomes chemistry, Inflammasomes drug effects, Inflammasomes immunology, Inflammation, Isodon chemistry, Mice, Mice, Inbred C57BL, Mice, Knockout, NIMA-Related Kinases antagonists & inhibitors, NIMA-Related Kinases immunology, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, NLR Family, Pyrin Domain-Containing 3 Protein immunology, Peritonitis genetics, Peritonitis immunology, Peritonitis pathology, Plant Extracts chemistry, Protein Binding, Signal Transduction, Anti-Inflammatory Agents pharmacology, Arthritis, Gouty drug therapy, Diabetes Mellitus, Type 2 drug therapy, Diterpenes, Kaurane pharmacology, NIMA-Related Kinases genetics, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Peritonitis drug therapy
- Abstract
Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori's anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.
- Published
- 2018
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