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

  • Front Immunol. 2022 May 19;13:880262. doi: 10.3389/fimmu.2022.880262.
Qiang Yu  1 ,  Honghu Tu  1 ,  Xueyi Yin  2 ,  Chang Peng  3  4 ,  Chuanyun Dou  3  4 ,  Wenhua Yang  3 ,  Wenbiao Wu  5 ,  Xiaotong Guan  5 ,  Jia Li  3  4 ,  Hexin Yan  6 ,  Yi Zang  2  3  5 ,  Haowen Jiang  3 ,  Qiang Xia  1  7  8
Affiliations
  • 1. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4. School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China.
  • 5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences (UCAS), Hangzhou, China.
  • 6. Department of Anesthesia, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 7. Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China.
  • 8. Shanghai Institute of Transplantation, Shanghai, China.
PMID: 35663990 DOI: 10.3389/fimmu.2022.880262
Abstract

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.

Keywords
SLC7A5; T cells activation and differentiation; autoimmune hepatitis (AIH); glutamine metabolism; mTOR signaling.
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