Autoimmune rheumatologic diseases
Michihito Kono, MD., PhD
Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University/ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
Objective: Glutaminase 1 (Gls1) is the first enzyme in glutaminolysis. We previously showed that the selective Gls1 inhibitor Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) suppresses Th17 cell development and suppresses experimental autoimmune encephalomyelitis (EAE). However, the involved mechanisms and whether inhibition of glutaminolysis can be useful in the treatment of systemic lupus erythematosus (SLE) remain unknown.
Methods: MRL/lpr mice were treated by BPTES or vehicle control and disease activity was examined. Then naïve 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 and EAE disease were investigated. The expression of hypoxia-inducible factor 1α (HIF1α) and the von Hippel–Lindau tumor suppressor protein (VHL) which degrades HiF1α were examined by qPCR and Western blot.
Results: MRL/lpr mice with BPTES improved autoimmune pathology in a Th17-dependent fashion. T cells from patients with SLE treated with BPTES displayed decreased Th17 differentiation. Using the conditional knockout mice we demonstrated that both the in vitro Th17 differentiation and the development of EAE depend on Gls1. Gls1 inhibition reduced the expression of HIF1α protein, while the expression levels of VHL were found to be increased suggesting excessive degradation of HIF1α.
Conclusion: We have provided evidence that inhibition of glutaminolysis can be used to treat patients with SLE and Th17-related autoimmune diseases. Mechanistically we showed that glutaminolysis inhibition suppresses Hif1α expression in Th17 cells by increasing VHL.