Normalization of CD4+ T Cell Metabolism Reverses Lupus

By Yiming Yin, Seung-Chul Choi, Zhiwei Xu, Daniel J. Perry, Howard R. Seay, B. Croker, E. Sobel, T. Brusko, L. Morel. Science Translational Medicine, 2015

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Systemic lupus erythematosus is associated with enhanced CD4+ T cell metabolism and can be reversed by metabolic modulators. Normalizing immune cell metabolism treats lupus Systemic lupus erythematosus (SLE) is an autoimmune disease where the immune system attacks normal, healthy tissues. CD4+ T cells are critical to SLE pathogenesis, but it has remained unclear if metabolism in these cells contributes to disease. Now, Yin et al. report that two metabolic pathways—glycolysis and mitochondrial oxidative metabolism—are elevated in cells from SLE patients as well as in mouse models of disease. What’s more, inhibitors of these pathways currently in the clinic—2-deoxy-d-glucose (2DG) and metformin—normalized T cell metabolism and decreased markers of SLE in animal models as well as in cells from SLE patients. These data suggest that inhibiting both glycolysis and mitochondrial metabolism could be a new therapeutic strategy for treating SLE. Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoreactive CD4+ T cells play an essential role. CD4+ T cells rely on glycolysis for inflammatory effector functions, but recent studies have shown that mitochondrial metabolism supports their chronic activation. How these processes contribute to lupus is unclear. We show that both glycolysis and mitochondrial oxidative metabolism are elevated in CD4+ T cells from lupus-prone B6.Sle1.Sle2.Sle3 (TC) mice as compared to non-autoimmune controls. In vitro, both the mitochondrial metabolism inhibitor metformin and the glucose metabolism inhibitor 2-deoxy-d-glucose (2DG) reduced interferon-γ (IFN-γ) production, although at different stages of activation. Metformin also restored the defective interleukin-2 (IL-2) production by TC CD4+ T cells. In vivo, treatment of TC mice and other lupus models with a combination of metformin and 2DG normalized T cell metabolism and reversed disease biomarkers. Further, CD4+ T cells from SLE patients also exhibited enhanced glycolysis and mitochondrial metabolism that correlated with their activation status, and their excessive IFN-γ production was significantly reduced by metformin in vitro. These results suggest that normalization of T cell metabolism through the dual inhibition of glycolysis and mitochondrial metabolism is a promising therapeutic venue for SLE.

Subfields: Immunology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/d82949992cb70d065888b5414432f603da7ff29b

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In Immunology

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