2. Academic Validation
  3. Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

  • Cell Metab. 2023 Jul 11;35(7):1132-1146.e9. doi: 10.1016/j.cmet.2023.05.001.
Benjamin J Jenkins 1,  Julianna Blagih 2,  Fernando M Ponce-Garcia 1,  Mary Canavan 3,  Nancy Gudgeon 4,  Simon Eastham 5,  David Hill 5,  Megan M Hanlon 3,  Eric H Ma 6,  Emma L Bishop 4,  April Rees 1,  James G Cronin 1,  Elizabeth C Jury 7,  Sarah K Dimeloe 4,  Douglas J Veale 8,  Catherine A Thornton 1,  Karen H Vousden 9,  David K Finlay 10,  Ursula Fearon 3,  Gareth W Jones 5,  Linda V Sinclair 11,  Emma E Vincent 12,  Nicholas Jones 13
Affiliations

Affiliations

  • 1 Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK.
  • 2 The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; University of Montreal, Maisonneuve-Rosemont Hospital Research Centre, 5414 Assomption Blvd, Montreal, QC H1T 2M4, Canada.
  • 3 Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland.
  • 4 Institute of Immunology and Immunotherapy, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • 5 Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK.
  • 6 Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA; Rheos Medicines, Cambridge, MA, USA.
  • 7 Centre for Rheumatology Research, Division of Medicine, University College London, London, UK.
  • 8 EULAR Centre of Excellence, Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin, Ireland.
  • 9 The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 10 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland.
  • 11 Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
  • 12 School of Translational Health Sciences, University of Bristol, Dorothy Hodgkin Building, Bristol BS1 3NY, UK; Integrative Epidemiology Unit, School of Population Health Science, University of Bristol, Bristol BS8 2BN, UK.
  • 13 Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK. Electronic address: [email protected].
PMID: 37230079 DOI: 10.1016/j.cmet.2023.05.001
Abstract

Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among Others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity.

Keywords

CD4 T cell; T cell; autoimmunity; canagliflozin; gliflozins; human; immunometabolism.

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