Glutaminase 1 Inhibition Reduces Glycolysis and Ameliorates Lupus‐like Disease in MRL / lpr Mice and Experimental Autoimmune Encephalomyelitis

作者：Michihito Kono, Nobuya Yoshida, Kayaho Maeda, Abel Suárez‐Fueyo, Vasileios C. Kyttaris, George C. Tsokos · 发表于：Arthritis & Rheumatology · 年份：2019 · DOI：10.1002/art.41019 · 被引用次数：110 · 研究领域：Cancer, Hypoxia, and Metabolism、High Altitude and Hypoxia、interferon and immune responses

OBJECTIVE: Glutaminase 1 (Gls1) is the first enzyme in glutaminolysis. The selective Gls1 inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) suppresses Th17 development and ameliorates experimental autoimmune encephalomyelitis (EAE). The present study was undertaken to investigate whether inhibition of glutaminolysis is beneficial for the treatment of systemic lupus erythematosus (SLE), and the involved mechanisms. METHODS: MRL/lpr mice were treated with BPTES or vehicle control, and disease activity was examined. Then naive CD4+ T cells from patients with SLE were cultured under Th17-polarizing conditions with BPTES or vehicle. Furthermore, using newly generated Gls1 conditional-knockout mice, in vitro Th17 differentiation was examined, and EAE was induced in the mice. Glutaminolysis and glycolysis were measured with an extracellular flux analyzer. The expression of hypoxia-inducible factor 1α (HIF-1α) was examined by Western blotting. RESULTS: Treatment of MRL/lpr mice with BPTES improved autoimmune pathology in a Th17-dependent manner. T cells from patients with SLE treated with BPTES displayed decreased Th17 differentiation (P < 0.05). Using the conditional-knockout mice, we demonstrated that both in vitro Th17 differentiation (P < 0.05) and the development of EAE were dependent on Gls1. Gls1 inhibition reduced glycolysis and the expression of HIF-1α protein, which induces glycolysis. CONCLUSION: We demonstrated that inhibition of glutaminolysi...