PMID- 35663990 OWN - NLM STAT- MEDLINE DCOM- 20220608 LR - 20220716 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation. PG - 880262 LID - 10.3389/fimmu.2022.880262 [doi] LID - 880262 AB - BACKGROUND: Autoimmune 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. METHODS: AIH 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. RESULTS: JHU083 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. CONCLUSIONS: We 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. CI - Copyright (c) 2022 Yu, Tu, Yin, Peng, Dou, Yang, Wu, Guan, Li, Yan, Zang, Jiang and Xia. FAU - Yu, Qiang AU - Yu Q AD - Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Tu, Honghu AU - Tu H AD - Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Yin, Xueyi AU - Yin X AD - School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Peng, Chang AU - Peng C AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China. FAU - Dou, Chuanyun AU - Dou C AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China. FAU - Yang, Wenhua AU - Yang W AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. FAU - Wu, Wenbiao AU - Wu W AD - School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences (UCAS), Hangzhou, China. FAU - Guan, Xiaotong AU - Guan X AD - School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences (UCAS), Hangzhou, China. FAU - Li, Jia AU - Li J AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China. FAU - Yan, Hexin AU - Yan H AD - Department of Anesthesia, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Zang, Yi AU - Zang Y AD - School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. AD - School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences (UCAS), Hangzhou, China. FAU - Jiang, Haowen AU - Jiang H AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. FAU - Xia, Qiang AU - Xia Q AD - Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. AD - Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China. AD - Shanghai Institute of Transplantation, Shanghai, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220519 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0RH81L854J (Glutamine) RN - 11028-71-0 (Concanavalin A) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Concanavalin A MH - Glutamine MH - *Hepatitis, Autoimmune MH - Humans MH - Mammals MH - Mice MH - Mice, Inbred C57BL MH - TOR Serine-Threonine Kinases MH - Th17 Cells PMC - PMC9160195 OTO - NOTNLM OT - SLC7A5 OT - T cells activation and differentiation OT - autoimmune hepatitis (AIH) OT - glutamine metabolism OT - mTOR signaling COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/06/07 06:00 MHDA- 2022/06/09 06:00 PMCR- 2022/01/01 CRDT- 2022/06/06 14:08 PHST- 2022/02/21 00:00 [received] PHST- 2022/04/21 00:00 [accepted] PHST- 2022/06/06 14:08 [entrez] PHST- 2022/06/07 06:00 [pubmed] PHST- 2022/06/09 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.880262 [doi] PST - epublish SO - Front Immunol. 2022 May 19;13:880262. doi: 10.3389/fimmu.2022.880262. eCollection 2022.