Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s Syndrome

Abstract

Previous studies have shown that abnormal metabolic reprogramming in CD4+ T cells could explain the occurrence of several autoimmune disorders, including Sjogren’s syndrome (SS). However, therapeutic targets of the abnormal metabolism of CD4+ T cells remain to be explored. Here, we report that glutaminase 1 (Gls1), a pivotal factor in glutaminolysis, might be involved in the pathogenesis of SS. The expression of Gls1 was upregulated in infiltrated labial CD4+ T cells and circulating CD4+ T cells of SS patients. Inhibiting Gls1 with BPTES significantly abolished the proliferation rate, as indicated by EdU, CFSE, and Western blot analyses. Additionally, BPTES downregulated the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) values of activated CD4+ T cells from SS mice. In vivo, we injected different doses of BPTES into SS-like NOD/Ltj mice and found that 10 mg/kg BPTES significantly restored the salivary flow rate. Histological and qRT–PCR analyses showed that this concentration of BPTES attenuated lymphocytic infiltration and the numbers of PCNA-positive cells and CD4+ T cells. The proportions of IFNγ-producing cells and IL-17A-producing cells and the expression of several proinflammatory cytokines, including IFNγ and IL-17A, were also affected in the salivary glands of SS-like mice. Cytokine production in circulating serum was analyzed and showed that BPTES downregulated the effector functions of Th17 cells and Th1 cells. Collectively, these results indicate a positive relationship between Gls1 and SS development. Pharmacological inhibition of Gls1 with BPTES could normalize the effector functions of CD4+ T cells and effectively attenuate the symptoms of SS.

HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome

“…In our previous study, we showed that both CD4 + T-cell activation and Th17 differentiation depend on the glycolytic metabolic pathway, and that the application of the glycolytic inhibitor 2-DG could effectively reduce the infiltration of CD4 + T cells in the submandibular gland of NOD/ShiLtj mice (Fu et al, 2020). In our recent study, we showed that the proinflammatory function of CD4 + T cells was associated with the glutamine metabolic pathway and that inhibition of glutaminase 1 alleviated SS-like symptoms in NOD/ShiLtj mice (Fu et al, 2022). Notably, ingested glucose and glutamine not only provide energy to cells, but also serve as a source of carbon for cholesterol synthesis by T cells.…”

Metabolism in stem cell driven leukaemia: parallels between haematopoiesis and immunity

“…Blocking glutaminolysis using BPTES or CB839 (Telaglenastat) has shown promising results in rheumatoid arthritis 60 , experimental autoimmune encephalomyelitis (EAE) 61 , and Sjogren's Syndrome 62 . Targeting the glutamine-cysteine antiporter has also shown promise in EAE 63 .…”

Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects

“…The mechanism is based on a reduction of Th17 differentiation of CD4 + T cells by inhibiting GLS1, glycolysis, and CD4 + T-cell differentiation in vitro by reducing the level of HIF1a protein, a key metabolic sensor in Th17 cells (9) (Table 1). Both in vivo and in vitro experiments have demonstrated that the GLS1 inhibitor BPTES normalized the effector function of CD4 + T cells and effectively improved the dysregulation of exocrine glands in Sjogren's syndrome (SS) (98). Inhibition of GLS1 by BPTES improves glycolysis and oxidative phosphorylation (OXPHOS) in SS-like CD4 + T cells and thus slows the progression of SS (98) (Table 1).…”