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Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation

文献类型：期刊论文

作者Yu, Qiang8; Tu, Honghu8; Yin, Xueyi7; Peng, Chang5,6; Dou, Chuanyun5,6; Yang, Wenhua6; Wu, Wenbiao4; Guan, Xiaotong4; Li, Jia5,6; Yan, Hexin3
刊名FRONTIERS IN IMMUNOLOGY
出版日期2022-05-19
卷号13页码:13
关键词glutamine metabolism autoimmune hepatitis (AIH) T cells activation and differentiation mTOR signaling
ISSN号1664-3224
DOI10.3389/fimmu.2022.880262
通讯作者Zang, Yi(yzang@simm.ac.cn) ; Jiang, Haowen(haowenjiang@simm.ac.cn) ; Xia, Qiang(xiaqiang@shsmu.edu.cn)
英文摘要BackgroundAutoimmune hepatitis (AIH) is mediated by a cascade of T cell-mediated events directed at liver cells and persistent inflammation within the liver can eventually result in liver cirrhosis. Targeting glutamine metabolism has an impact on T cell activation and differentiation. However, the effect of glutamine metabolism blocking upon AIH remains unknown. We use glutaminase antagonist 6-diazo-5-oxo-L-norleucine (DON) for in vitro assays and its prodrug 2-(2-amino-4-methylpentanamido)-DON (JHU083) for in vivo assays to investigate the potential therapeutic effect and molecular mechanism of glutamine metabolism blocking in an AIH murine model. MethodsAIH mice were treated with JHU083 or vehicle before concanavalin A (ConA) administration, and disease severity was examined. Then activation and differentiation [including Th1/Th17 cells and cytotoxic T lymphocytes (CTL)] of T cells from Vehicle-WT, JHU083-AIH and Vehicle-AIH mice were tested. Furthermore, in vitro T cell activation and differentiation were measured using separated splenocytes stimulated with ConA with or without DON. The activation and differentiation of T cells were tested using flow cytometry, qRT-PCR and ELISA. Phosphorylation level of mammalian target of rapamycin (mTOR) and 70 kDa ribosomal protein S6 kinase (P70S6K) were examined by western blotting. ResultsJHU083 and DON significantly suppressed the activation of T cells and inhibited the differentiation of Th1/Th17 cells and CTL in vivo and in vitro. Besides, we demonstrated that glutamine metabolism blocking inhibited T cells activation and differentiation through decreasing the mRNA expression of amino acid transporter solute carrier family 7 member 5 (SLC7A5) and mitigating the activation of mTOR signaling. ConclusionsWe proved that targeting glutamine metabolism represents a potential new treatment strategy for patients with AIH and other T cell-mediated disease. Mechanistically, we demonstrated that glutamine metabolism blocking inhibits T cells activation and suppresses the differentiation of Th1/Th17 cells and CTL.
WOS关键词CONCANAVALIN-A MODEL ; AMINO-ACID-TRANSPORT ; REGULATES MTOR
资助项目National Key R&D Program of China[2018YFA0108200] ; National Natural Science Foundation of China[32000525] ; 'Three-Year Action Plan for Promoting Clinical Skills and Clinical Innovation in Municipal Hospitals' Key Supporting Projects[SHDC2020CR5012] ; Major clinical research projects[SHDC2020CR2003A]
WOS研究方向Immunology
语种英语
WOS记录号WOS:000806200900001
出版者FRONTIERS MEDIA SA
源URL[http://119.78.100.183/handle/2S10ELR8/301428]  
专题新药研究国家重点实验室
通讯作者Zang, Yi; Jiang, Haowen; Xia, Qiang
作者单位1.Shanghai Inst Transplantat, Shanghai, Peoples R China
2.Shanghai Engn Res Ctr Transplantat & Immunol, Shanghai, Peoples R China
3.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Anesthesia, Shanghai, Peoples R China
4.Univ Chinese Acad Sci UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharm, Beijing, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
8.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Liver Surg, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Yu, Qiang,Tu, Honghu,Yin, Xueyi,et al. Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation[J]. FRONTIERS IN IMMUNOLOGY,2022,13:13.
APA Yu, Qiang.,Tu, Honghu.,Yin, Xueyi.,Peng, Chang.,Dou, Chuanyun.,...&Xia, Qiang.(2022).Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation.FRONTIERS IN IMMUNOLOGY,13,13.
MLA Yu, Qiang,et al."Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation".FRONTIERS IN IMMUNOLOGY 13(2022):13.

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来源：上海药物研究所

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