Quercetin Impedes Th17 Cell Differentiation to Mitigate Arthritis Involving PPAR gamma-Driven Transactivation of SOCS3 and Redistribution Corepressor SMRT from PPAR gamma to STAT3

作者全名："Yang, Yan; Shi, Gao-Na; Wu, Xin; Xu, Min; Chen, Cheng-Juan; Zhou, Yu; Wei, Ya-Zi; Wu, Lei; Cui, Fen-Fang; Sun, Lan; Zhang, Tian-Tai"

作者地址："[Yang, Yan; Shi, Gao-Na; Chen, Cheng-Juan; Zhou, Yu; Wei, Ya-Zi; Wu, Lei; Sun, Lan; Zhang, Tian-Tai] Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing, Peoples R China; [Yang, Yan; Xu, Min; Cui, Fen-Fang] Southwest Jiaotong Univ, Chongqing Med Univ, Peoples Hosp Chengdu 3, Dept Pharm,Affiliated Hosp,Chengdu Hosp 2, Chengdu, Peoples R China; [Wu, Xin] Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing, Peoples R China; [Wu, Xin] Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing, Peoples R China"

通信作者："Sun, L; Zhang, TT (通讯作者)，Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing, Peoples R China."

来源：MOLECULAR NUTRITION & FOOD RESEARCH

ESI学科分类：AGRICULTURAL SCIENCES

WOS号：WOS:000781656800001

JCR分区：Q1

影响因子：5.2

年份：2022

卷号：66

期号：12

开始页：　

结束页：　

文献类型：Article

关键词：arthritis; PPAR gamma; quercetin; SOCS3/STAT3 pathway; Th17 cell

摘要："Scope: Quercetin (QU) is one of the most abundant flavonoids in plants and has attracted the attention of researchers because of its remarkable antirheumatoid arthritis (RA) effects and extremely low adverse reactions. However, the underlying mechanism needs further study. Methods and results: Flow cytometry, immunofluorescence, enzyme linked immunosorbent assay (ELISA), and quantitative real-time polymerase chain reaction (qRT-PCR) reveal the obvious inhibitory effects of QU on Th17 cell differentiation in arthritic mice. More importantly, QU markedly limits the development of Th17 cell polarization, which is virtually compromised by the treatment with peroxisome proliferator activated receptor gamma (PPAR gamma) inhibitor Orr GW9662 and knockdown of PPAR gamma. Additionally, molecular dynamics simulation and immunofluorescence exhibit QU directly binds to PPAR gamma and increases PPAR gamma nuclear translocation. Besides, QU confers its moderation effect on suppressor of cytokine signaling protein (SOCS3)/sign al transducer and activator of transcription 3 (STAT3) axis partially depending on PPAR gamma. Furthermore, coimmunoprecipitation shows QU redistributes the corepressor silencing mediator for retinoid and thyroid-hormone receptors (SMRT) from PPAR gamma to STAT3. Finally, the inhibition of Th17 response and the antiarthritic effect of QU are nullified by GW9662 treatment in arthritic mice. Conclusion: QU targets PPAR gamma and consequently inhibits Th17 cell differentiation by dual inhibitory activity of STAT3 to exert antiarthritic effect. The findings facilitate its development and put forth a stage for uncovering the mechanism of other naturally occurring compounds with chemical structures similar to QU."

基金机构："National Key R&D Program of China [2020YFA0908004]; National Natural Science Foundation of China [81703781, 81973338]"

基金资助正文："This work was supported by the National Key R&D Program of China (2020YFA0908004) and the National Natural Science Foundation of China (81703781, 81973338)."