Myricetin inhibits NLRP3 inflammasome activation via reduction of ROS-dependent ubiquitination of ASC and promotion of ROS-independent NLRP3 ubiquitination

Hanwen Chen; Hui Lin; Shujun Xie; Bo Huang; Yufeng Qian; Kelie Chen; Yuequn Niu; Han-Ming Shen; Jianting Cai; Peiwei Li; Jianhang Leng; Hao Yang; Dajing Xia; Yihua Wu

doi:10.1016/j.taap.2018.12.019

Myricetin inhibits NLRP3 inflammasome activation via reduction of ROS-dependent ubiquitination of ASC and promotion of ROS-independent NLRP3 ubiquitination

Toxicol Appl Pharmacol. 2019 Feb 15:365:19-29. doi: 10.1016/j.taap.2018.12.019. Epub 2018 Dec 27.

Authors

Hanwen Chen¹, Hui Lin², Shujun Xie³, Bo Huang³, Yufeng Qian⁴, Kelie Chen², Yuequn Niu³, Han-Ming Shen⁵, Jianting Cai⁶, Peiwei Li⁶, Jianhang Leng⁷, Hao Yang³, Dajing Xia⁸, Yihua Wu⁹

Affiliations

¹ Department of Toxicology, School of Public Health, Zhejiang University, Zhejiang, Hangzhou 310058, China; Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou 310009, China.
² Department of Toxicology, School of Public Health, Zhejiang University, Zhejiang, Hangzhou 310058, China; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Zhejiang, Hangzhou 310006, China.
³ Department of Toxicology, School of Public Health, Zhejiang University, Zhejiang, Hangzhou 310058, China.
⁴ Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou 310006, China.
⁵ Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore.
⁶ Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou 310009, China.
⁷ Central Laboratory, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou 310006, China.
⁸ Department of Toxicology, School of Public Health, Women's Hospital, School of Medicine, Zhejiang University, Zhejiang, Hangzhou 310058, China. Electronic address: dxia@zju.edu.cn.
⁹ Department of Toxicology, School of Public Health, Zhejiang University, Zhejiang, Hangzhou 310058, China. Electronic address: georgewu@zju.edu.cn.

PMID: 30594691
DOI: 10.1016/j.taap.2018.12.019

Abstract

Myricetin is a plant-derived flavonoid that exhibits diverse pharmacological properties. The NLRP3 (NLR family, pyrin domain-containing 3 protein) inflammasome is a cytosolic multiprotein complex that plays a critical role in the innate immune response and pathogenesis of multiple inflammatory disorders. The present study found that myricetin inhibited NLRP3 inflammasome assembly via promotion of reactive oxygen species (ROS)-independent ubiquitination of NLRP3 and reduction of ROS-dependent ubiquitination of ASC (apoptosis-associated speck-like protein containing a CARD), which disrupted the interaction between ASC and NLRP3 and inhibited ASC oligomerization. This effect was further confirmed in vivo using mouse models of lipopolysaccharide (LPS)-induced sepsis and alum-induced peritonitis. These results suggest the therapeutic value of myricetin by targeting NLRP3-driven inflammatory diseases.

Keywords: Myricetin; NLRP3 inflammasome; Reactive oxygen species; Ubiquitination.

Publication types

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

MeSH terms

Animals
Anti-Inflammatory Agents / pharmacology*
CARD Signaling Adaptor Proteins / immunology
CARD Signaling Adaptor Proteins / metabolism*
Disease Models, Animal
Flavonoids / pharmacology*
Humans
Inflammasomes / drug effects*
Inflammasomes / immunology
Inflammasomes / metabolism
Macrophages, Peritoneal / drug effects*
Macrophages, Peritoneal / immunology
Macrophages, Peritoneal / metabolism
Male
Mice, Inbred C57BL
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
NLR Family, Pyrin Domain-Containing 3 Protein / immunology
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Peritonitis / immunology
Peritonitis / metabolism
Peritonitis / prevention & control*
Reactive Oxygen Species / metabolism*
Sepsis / immunology
Sepsis / metabolism
Sepsis / prevention & control*
Signal Transduction / drug effects
THP-1 Cells
Ubiquitination

Substances

Anti-Inflammatory Agents
CARD Signaling Adaptor Proteins
Flavonoids
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Pycard protein, mouse
Reactive Oxygen Species
myricetin