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

Kono, M;Yoshida, N;Maeda, K;Surez-Fueyo, A;Kyttaris, VC;Tsokos, GC;

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). However, whether inhibition of glutaminolysis is beneficial for the treatment of systemic lupus erythematosus (SLE) and the involved mechanisms are still unknown. MRL/lpr mice were treated by BPTES or vehicle control and disease activity was examined. Then nave CD4+ T cells from patients with SLE were cultured under Th17 conditions with BPTES or the vehicle. Furthermore, using newly generated Gls1 conditional knockout mice in IL-17 producing cells, in vitro Th17 differentiation were examined and EAE was induced in these mice. Glutaminolysis and glycolysis were measured by extracellular flux analyzer. The expression of hypoxia-inducible factor 1 (HIF1) was also examined by Western blotting. Treatment of MRL/lpr mice with BPTES improved autoimmune pathology in a Th17-dependent fashion. T cells from patients with SLE treated with BPTES display decreased Th17 differentiation (P < 0.05). Using the conditional knockout mice we demonstrate that both the in vitro Th17 differentiation (P < 0.05) and the development of EAE depend on Gls1. Gls1 inhibition reduced glycolysis and the expression of HIF1 protein which induces glycolysis. We have demonstrated that inhibition of glutaminolysis represents a potential new treatment strategy for patients with SLE and Th17-related autoimmune diseases. Mechanistically we have shown that inhibition of glutaminolysis affects the glycolysis pathway by reducing Hif1 protein in Th17 cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.