title: Normalization of CD4+ T cell metabolism reverses lupus.
abstract: 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.
authors: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Yiming
authors: Y
authors: Yin
authors: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Seung-Chul
authors: SC
authors: Choi
authors: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Zhiwei
authors: Z
authors: Xu
authors: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Daniel J
authors: DJ
authors: Perry
authors: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Howard
authors: H
authors: Seay
authors: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Byron P
authors: BP
authors: Croker
authors: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Eric S
authors: ES
authors: Sobel
authors: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors: Todd M
authors: TM
authors: Brusko
authors: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA. morel@ufl.edu.
authors: Laurence
authors: L
authors: Morel
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D003847:Deoxyglucose / Q000627:therapeutic use; D004195:Disease Models, Animal; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000378:metabolism*; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D010641:Phenotype
chemical_list: D008687:Metformin; D003847:Deoxyglucose