Inhibition of glutaminolysis ameliorates lupus by regulating T and B cell subsets and downregulating the mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in MRL/lpr mice

  • Int Immunopharmacol. 2022 Sep 13;112:109133. doi: 10.1016/j.intimp.2022.109133.
Xiaomei Zhang  1 ,  Gang Wang  2 ,  Ying Bi  3 ,  Zhihang Jiang  1 ,  Xiaofei Wang  1
Affiliations
  • 1. Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang 110022, China.
  • 2. Department of Neurosurgery, the First Hospital of China Medical University, Shenyang 110001, China. Electronic address: [email protected].
  • 3. Department of Rheumatology and Immunology, the Fourth Hospital of China Medical University, Shenyang 110001, China.
PMID: 36113317 DOI: 10.1016/j.intimp.2022.109133
Abstract

Background and aim of the study: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by lymphocyte imbalance. The differentiation and function of T and B cells receive regulation from intracellular energy metabolism. Herein, we aimed to investigate glutamine metabolism levels in SLE and explore the effects of modulating glutamine metabolism on T and B cell subsets and related signaling pathways in MRL/lpr lupus mice.

Methods: We assessed intracellular glutamine metabolism in SLE patients and MRL/lpr mice by measuring intracellular glutamate and Glutaminase 1 (GLS1) protein levels. Intraperitoneal injection of the GLS1 inhibitor CB839 was performed to reduce glutamine metabolism and lupus-like manifestations in MRL/lpr mice were evaluated. The proportions and numbers of T and B cell subsets were determinedvia flow cytometry. Pathway-related proteins were detected using western blotting.

Results: In this study, we reported that glutamine metabolism levels were aberrantly elevated in splenic mononuclear cells from MRL/lpr lupus mice, as well as in peripheral blood mononuclear cells (PBMCs) of SLE patients. Inhibition of glutamine metabolism by CB839 treatment for 8 weeks alleviated the lupus-like manifestations in MRL/lpr mice, including the kidney lesions, urinary protein/creatinine ratio, spleen index, and serum IgG1. Meanwhile, CB839 treatment ameliorated the depletion of IL-10 producing B cells (B10) and adjusted the Th1/TH2 and TH17/Treg imbalance. The inhibition of GLS1 by CB839 reduced the numbers of follicular helper T (TfH) cells and activated B cells in lupus mice. The proportions of mature B cells and plasma cells were not affected. Furthermore, the hyperactivated mTOR/p70S6K/4EBP1 and NLRP3/Caspase-1/IL-1β pathways in MRL/lpr mice were reversed by CB839 treatment.

Conclusion: Our study confirmed the presence of abnormal intracellular glutamine metabolism in SLE and revealed potential therapeutic targets for this disease.

Keywords
B cell subsets; CB839; Glutamine metabolism; Lupus nephritis; NLRP3 pathway; Systemic lupus erythematosus; T cell subsets; mTOR pathway.
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