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

• Published in: International immunopharmacology Vol. 112; p. 109133
• Main Authors: Zhang, Xiaomei, Wang, Gang, Bi, Ying, Jiang, Zhihang, Wang, Xiaofei
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.11.2022
• Subjects: B cell subsets; CB839; Glutamine metabolism; Lupus nephritis; mTOR pathway; NLRP3 pathway; Systemic lupus erythematosus; T cell subsets; CB839; Systemic lupus erythematosus; Glutamine metabolism; mTOR pathway; NLRP3 pathway; Lupus nephritis; B cell subsets; T cell subsets
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2022.109133

•Herein, intracellular glutamine metabolism level in lupus was revealed.•In this study, a direct detection of intracellular metabolites was used to evaluate the glutamine metabolism level, avoiding the metabolic environmental difference between in vitro culture and in vivo and reflected a more intuitive metabolic profile.•Evaluated the effect of regulation of glutamine metabolism on B cell subsets in MRL/lpr mice for the first time.•Previous studies have shown that inhibiting glutamine metabolism may be beneficial to lupus, and this study conducted a more in-depth study of the mechanism. Inhibition of glutamine metabolism could regulate mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in lupus. 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. 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. 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. Our study confirmed the presence of abnormal intracellular glutamine metabolism in SLE and revealed potential therapeutic targets for this disease.