Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: Autoreactive CD4 T cells are key effectors in Systemic Lupus Erythematosus (SLE). Cell metabolism is an important checkpoint for T cell activationand differentiation. Both Anaerobic glycolysis and mitochondrial oxidative phosphorylation are necessary for effector CD4 T cell differentiation and inflammatory cytokine production. We hypothesized that 1) SLE T cells have metabolic defects that impair their functions; 2) Targeting CD4 T cell metabolism may abrogate CD4 T cell inflammatory functions and reduce disease symptoms in SLE mice; 3) The functions of CD4 T cells from SLE patients can be normalized by treatment with metabolic inhibitors.
Methods: CD4 T cells from lupus-prone mice and controls, as well as CD4 T cells obtained from SLE patients and healthy controls were treated with metformin or 2-DG, or a combination of the two. Several models of lupus-prone mice were treated with these drugs, either before or after disease onset. Glycolysis (extracellular acidification rate; ECAR) and oxygen consumption rate (OCR) were measured in CD4 T cells with an Extracellular Flux Analyzer. CD4 T cell activation and effector subsets were analyzed by flow cytometry. Disease progression was assessed by measuring serum anti-dsDNA IgG and anti-nuclear autoantibodies by ELISA and immunofluorescence, as well as renal histopathology.
Results: CD4 T cells from lupus mice have a significantly higher metabolism with increase in both ECAR and OCR, as well as an enhanced mTOR activity as compared to control mice. To normalize T cell metabolism in these mice, we used metformin, which activates the AMPK pathway and inhibits mitochondrial oxygen consumption, and 2-DG, an inhibitor of glycolysis. In vitro, metformin blocked IFNγ production and enhanced Treg development. 2-DG also blocked IFNγ production, but only after T cell activation. In vivo, a combined treatment with metformin and 2-DG normalized T cell metabolism and reversed disease phenotypes, including T cell activation and effector functions, as well as autoantibody production in the B6.Sle1.Sle2.Sle3 and the NZB/WF1 spontaneous models, as well as the chronic graft-vs-host disease model. Renal pathology is pending. Neither treatment with metformin or 2-DG alone resulted in disease reversal. Further, CD4 T cells from SLE patients showed an enhanced metabolism as compared to healthy controls, and their excessive IFNγ production was significantly reduced by metformin.
Conclusion: The combination of a glucose inhibitor with metformin restores T cell functions and reverses disease in mouse models, while metformin treatment normalizes the function of T cells from lupus patients. We propose that T cell metabolism is a novel target for SLE treatment.
S. C. Choi,
E. S. Sobel,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-combination-of-metformin-and-2-deoxy-d-glucose-normalizes-cd4-t-cell-metabolism-and-functions-and-reverse-disease-in-murine-models-of-lupus/