Citations

3355 total record number
266 records this year

To narrow your search, use one or more of the following search menus below.

To search by keyword, you may search by type of cell/animal/assay/protein/research or publication.

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

Kono, M;Yoshida, N;Maeda, K;Suárez-Fueyo, A;Kyttaris, VC;Tsokos, GC;
Product: Pertussis Toxin from B. pertussis, Lyophilized in Buffer

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 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 were examined and EAE was induced in these mice. Glutaminolysis and glycolysis were measured by extracellular flux analyzer. The expression of hypoxia-inducible factor 1α (HIF1α) 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 HIF1α 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 Hif1α protein in Th17 cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

PubMed ID: 31233276