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

Abstract

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 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 HIF‐1α protein in Th17 cells.

T Cell Metabolism: A New Perspective on Th17/Treg Cell Imbalance in Systemic Lupus Erythematosus

“…(4) Increased glutaminolysis: There is more expression of ICER, the transcriptional factor that promotes glutaminolysis and Th17 generation in CD4 + T cells from SLE patients than in healthy controls (39). Glutaminase 1 inhibition improved autoimmune pathology in MRL/lpr mice, and suppressed Th17 differentiation of T cells from patients with SLE but not in those from healthy donors (40). Those data suggested increased glutaminolysis in SLE T cells.…”

Metabolic determinants of lupus pathogenesis

“…57 Accordingly, MRL/lpr mice treated with the GLS1 inhibitor BPTES showed attenuated lupus outcomes in a Th17dependent manner, and BPTES decreased the polarization of Th17 cells in SLE patients. 57 Specific tissue microenvironments such as tumors or the inflamed kidneys in lupus nephritis 178 their proliferation and class-switching. 179 These findings demonstrate that oxygen sensing and rapid switch to the corresponding metabolic program is an essential requirement of GC B cells.…”

“…Th17 cells have been implicated in lupus pathogenesis. 57 It is therefore tantalizing to predict that high glucose consumption may aggravate disease in lupus patients, a hypothesis that should be tested in mouse models. It should be noted that it is not known whether a reduction in glucose consumption has a protective effect in autoimmunity.…”

“…In the context of lupus, Gls1 inhibition with BPTES ameliorated lupus manifestations in MRL/lpr mice in a Th17-dependent manner. 57 It is unknown whether this treatment would be as effective in other models in which Th17 cells play a lesser role. The requirements for glutaminolysis have been recently examined for the GC reaction in a mouse model of lupus.…”

T cell Metabolism in Lupus

“…cell differentiation [88,92] and disease activity in animals subjected to experimental autoimmune encephalomyelitis (EAE). The glutaminase inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES)], also ameliorates the disease activity in MRL/lpr mice [93] (Table 1).…”