RESEARCH HIGHLIGHTS Nature Reviews Rheumatology advance online publication 3 March 2015; doi:10.1038/nrrheum.2015.24
CONNECTIVE TISSUE DISEASES
Can SLE be treated by altering T‑cell metabolism? The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of ex vivo CD4+ T cells were higher in 2‑month old (preclinical disease) spontaneous-lupus-prone mice (B6.Sle1. Sle2.Sle3.) than in wildtype mice, and this difference was even more pronounced in 9-month old (clinical signs of disease) mice. Polyclonal stimulation had a similar response in vitro, increasing mTOR complex 1 activity and IFN‑γ production, and reducing IL‑2 production, by the CD4+ T cells from the lupus-prone mice. These cells also had higher expression of glycolytic genes, such as Hif1a, and lower expression of the pyruvate oxidation inhibitor Pdk1. Confirming the mouse data, CD4+ T cells from patients with SLE also had higher ECAR and OCR than cells from healthy individuals, even though patients are treated with immunosuppressive
NATURE REVIEWS | RHEUMATOLOGY
drugs that reduce these rates when applied in vitro. Importantly, treatment of lupus-prone mice with metabolic inhibitors metformin and 2‑deoxyglucose reduced ECAR, OCR and early signs of lupus such as splenomegaly and the production of anti-double-stranded-DNA IgG and anti-nuclear autoantibodies. “Although metabolism of other immune cells was probably affected by the in vivo treatment,” notes Morel “our study shows that a normalization of the T‑cell phenotypes was associated with disease reversal.” Her hope now is that human T‑cell metabolism could be targeted “with existing drugs repurposed for the treatment of immune-related diseases.” NPG
“CD4+ T cell metabolism is hyperactive in lupus,” says Laurence Morel, lead author of a study now published in Science Translational Medicine. She states, “This study is a proof of principle—the first I think— that metabolism can be targeted to reverse a complex spontaneous autoimmune disease.” T‑cell function is known to be dependent on cellular metabolism as helper T cells are more glycolytic than regulatory T cells, and naive T cells activate glycolysis and mitochondrial metabolism in response to T‑cell receptor activation. Morel also coauthored an earlier study that identified Esrrg, a regulator of mitochondrial oxidative phosphorylation, as a lupus susceptibility gene in mice (locus Sle1c2). Armed with this knowledge, she says her group hypothesized “that lupus T cells are sustained by an enhanced metabolism and that metabolic inhibitors should alleviate disease by normalizing T‑cell metabolism.”
Nicholas J. Bernard Original article Yin, Y. et al. Normalization of CD4+ T cell metabolism reverses lupus Sci. Transl. Med. doi:10.1126/ scitranslmed.aaa0835
ADVANCE ONLINE PUBLICATION © 2015 Macmillan Publishers Limited. All rights reserved
CONNECTIVE TISSUE DISEASES
Can SLE be treated by altering T‑cell metabolism? The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of ex vivo CD4+ T cells were higher in 2‑month old (preclinical disease) spontaneous-lupus-prone mice (B6.Sle1. Sle2.Sle3.) than in wildtype mice, and this difference was even more pronounced in 9-month old (clinical signs of disease) mice. Polyclonal stimulation had a similar response in vitro, increasing mTOR complex 1 activity and IFN‑γ production, and reducing IL‑2 production, by the CD4+ T cells from the lupus-prone mice. These cells also had higher expression of glycolytic genes, such as Hif1a, and lower expression of the pyruvate oxidation inhibitor Pdk1. Confirming the mouse data, CD4+ T cells from patients with SLE also had higher ECAR and OCR than cells from healthy individuals, even though patients are treated with immunosuppressive
NATURE REVIEWS | RHEUMATOLOGY
drugs that reduce these rates when applied in vitro. Importantly, treatment of lupus-prone mice with metabolic inhibitors metformin and 2‑deoxyglucose reduced ECAR, OCR and early signs of lupus such as splenomegaly and the production of anti-double-stranded-DNA IgG and anti-nuclear autoantibodies. “Although metabolism of other immune cells was probably affected by the in vivo treatment,” notes Morel “our study shows that a normalization of the T‑cell phenotypes was associated with disease reversal.” Her hope now is that human T‑cell metabolism could be targeted “with existing drugs repurposed for the treatment of immune-related diseases.” NPG
“CD4+ T cell metabolism is hyperactive in lupus,” says Laurence Morel, lead author of a study now published in Science Translational Medicine. She states, “This study is a proof of principle—the first I think— that metabolism can be targeted to reverse a complex spontaneous autoimmune disease.” T‑cell function is known to be dependent on cellular metabolism as helper T cells are more glycolytic than regulatory T cells, and naive T cells activate glycolysis and mitochondrial metabolism in response to T‑cell receptor activation. Morel also coauthored an earlier study that identified Esrrg, a regulator of mitochondrial oxidative phosphorylation, as a lupus susceptibility gene in mice (locus Sle1c2). Armed with this knowledge, she says her group hypothesized “that lupus T cells are sustained by an enhanced metabolism and that metabolic inhibitors should alleviate disease by normalizing T‑cell metabolism.”
Nicholas J. Bernard Original article Yin, Y. et al. Normalization of CD4+ T cell metabolism reverses lupus Sci. Transl. Med. doi:10.1126/ scitranslmed.aaa0835
ADVANCE ONLINE PUBLICATION © 2015 Macmillan Publishers Limited. All rights reserved
