Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Benjamin J Jenkins¹, Julianna Blagih², Fernando M Ponce-Garcia¹, Mary Canavan³, Nancy Gudgeon⁴, Simon Eastham⁵, David Hill⁵, Megan M Hanlon³, Eric H Ma⁶, Emma L Bishop⁴, April Rees¹, James G Cronin¹, Elizabeth C Jury⁷, Sarah K Dimeloe⁴, Douglas J Veale⁸, Catherine A Thornton¹, Karen H Vousden⁹, David K Finlay¹⁰, Ursula Fearon³, Gareth W Jones⁵, Linda V Sinclair¹¹, Emma E Vincent¹², Nicholas Jones¹³

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: n.jones@swansea.ac.uk.

PMID: 37230079
DOI: 10.1016/j.cmet.2023.05.001

Free article

Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Benjamin J Jenkins et al. Cell Metab. 2023.

Free article

. 2023 Jul 11;35(7):1132-1146.e9.

doi: 10.1016/j.cmet.2023.05.001. Epub 2023 May 24.

Authors

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: n.jones@swansea.ac.uk.

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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Conflict of interest statement

Declaration of interests K.H.V. is on the board of directors and shareholder of Bristol Myers Squibb, a shareholder of GRAIL, and on the science advisory board of PMV Pharma, RAZE Therapeutics, Volastra Pharmaceuticals, and Ludwig Cancer. She is a co-founder and consultant of Faeth Therapeutics, funded by Khosla Ventures. She has been in receipt of research funding from Astex Pharmaceuticals and AstraZeneca and contributed to CRUK Cancer Research Technology filing of patent application WO/2017/144877.

Comment in

Canagliflozin disrupts T cell activation.
Wang M. Wang M. Nat Rev Nephrol. 2023 Aug;19(8):478. doi: 10.1038/s41581-023-00739-4. Nat Rev Nephrol. 2023. PMID: 37369855 No abstract available.
Repurposing SGLT2 inhibitors for autoimmune diseases? YES, WE MAY!
Certo M, Niven J, Mauro C. Certo M, et al. Cell Chem Biol. 2023 Sep 21;30(9):1009-1011. doi: 10.1016/j.chembiol.2023.07.020. Cell Chem Biol. 2023. PMID: 37738952

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Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

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Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

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