Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity

Hongbin He; Hua Jiang; Yun Chen; Jin Ye; Aoli Wang; Chao Wang; Qingsong Liu; Gaolin Liang; Xianming Deng; Wei Jiang; Rongbin Zhou

doi:10.1038/s41467-018-04947-6

Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity

Nat Commun. 2018 Jun 29;9(1):2550. doi: 10.1038/s41467-018-04947-6.

Authors

Hongbin He^{1

2}, Hua Jiang¹, Yun Chen³, Jin Ye¹, Aoli Wang⁴, Chao Wang¹, Qingsong Liu⁴, Gaolin Liang⁵, Xianming Deng⁶, Wei Jiang⁷, Rongbin Zhou^{8

9}

Affiliations

¹ Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
² Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, 230027, China.
³ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
⁴ High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, 230031, China.
⁵ Hefei National Laboratory for Physical Sciences at Microscale, Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China.
⁶ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. xmdeng@xmu.edu.cn.
⁷ Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China. ustcjw@ustc.edu.cn.
⁸ Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China. zrb1980@ustc.edu.cn.
⁹ Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, 230027, China. zrb1980@ustc.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / isolation & purification
Anti-Inflammatory Agents / pharmacology*
Arthritis, Gouty / drug therapy*
Arthritis, Gouty / genetics
Arthritis, Gouty / immunology
Arthritis, Gouty / pathology
Blood Glucose / metabolism
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / genetics
Diabetes Mellitus, Type 2 / immunology
Diabetes Mellitus, Type 2 / pathology
Disease Models, Animal
Diterpenes, Kaurane / isolation & purification
Diterpenes, Kaurane / pharmacology*
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 / genetics*
NIMA-Related Kinases / immunology
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
NLR Family, Pyrin Domain-Containing 3 Protein / genetics*
NLR Family, Pyrin Domain-Containing 3 Protein / immunology
Peritonitis / drug therapy*
Peritonitis / genetics
Peritonitis / immunology
Peritonitis / pathology
Plant Extracts / chemistry
Protein Binding
Signal Transduction

Substances

Anti-Inflammatory Agents
Blood Glucose
Diterpenes, Kaurane
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Plant Extracts
oridonin
NIMA-Related Kinases
Nek7 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding