Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Benjamin J Jenkins; Julianna Blagih; Fernando M Ponce-Garcia; Mary Canavan; Nancy Gudgeon; Simon Eastham; David Hill; Megan M Hanlon; Eric H Ma; Emma L Bishop; April Rees; James G Cronin; Elizabeth C Jury; Sarah K Dimeloe; Douglas J Veale; Catherine A Thornton; Karen H Vousden; David K Finlay; Ursula Fearon; Gareth W Jones; Linda V Sinclair; Emma E Vincent; Nicholas Jones

doi:10.1016/j.cmet.2023.05.001

Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Benjamin J Jenkins, Julianna Blagih, Fernando M Ponce-Garcia, Mary Canavan, Nancy Gudgeon, Simon Eastham, David Hill, Megan M Hanlon, Eric H Ma, Emma L Bishop, April Rees, James G Cronin, Elizabeth C Jury, Sarah K Dimeloe, Douglas J Veale, Catherine A Thornton, Karen H Vousden, David K Finlay, Ursula Fearon, Gareth W JonesLinda V Sinclair, Emma E Vincent, Nicholas Jones^*

^*Corresponding author for this work

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	1132-1146.e9
Number of pages	24
Journal	Cell Metabolism
Volume	35
Issue number	7
Early online date	24 May 2023
DOIs	https://doi.org/10.1016/j.cmet.2023.05.001
Publication status	Published - 11 Jul 2023

Bibliographical note

Acknowledgments:
We thank D.O.F. Skibinski, O. Bodger, A. Floudas, and S. Bain for useful discussion, A. Howden for proteomics advice, T. Jovic, E. Combellack, C. DeCourcey, K. Hawkins, and A. Tang for phlebotomy and all blood donors for their contribution to this work. B.J.J. is funded by a Swansea University Research Excellence Scholarship. G.W.J. is funded by a Versus Arthritis Career Development Fellowship (20305). J.B. was funded by a Canadian Institute for Health Research Postdoctoral Fellowship and the Kuok Family Postdoctoral Fellowship. E.E.V. is supported by a Diabetes UK RD Lawrence Fellowship (17/0005587) and by Cancer Research UK (C18281/A29019). This work was funded by a MRC New Investigator Research Grant (MR/X000095/1) awarded to N.J. We would like to acknowledge the FingerPrints Proteomics Facility at the University of Dundee, which is supported by the “Wellcome Trust Technology Platform” award (097945/B/11/Z). We thank the Metabolomics Facility at the Francis Crick Institute for their support.

Copyright:
© 2023 The Author(s). Published by Elsevier Inc.

Keywords

Humans
Canagliflozin/pharmacology
Diabetes Mellitus, Type 2/drug therapy
Autoimmunity
T-Lymphocytes
Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
Autoimmune Diseases/drug therapy
Hypoglycemic Agents/pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Jenkins, B. J., Blagih, J., Ponce-Garcia, F. M., Canavan, M., Gudgeon, N., Eastham, S., Hill, D., Hanlon, M. M., Ma, E. H., Bishop, E. L., Rees, A., Cronin, J. G., Jury, E. C., Dimeloe, S. K., Veale, D. J., Thornton, C. A., Vousden, K. H., Finlay, D. K., Fearon, U., ... Jones, N. (2023). Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity. Cell Metabolism, 35(7), 1132-1146.e9. https://doi.org/10.1016/j.cmet.2023.05.001

@article{579485aa62a8449f83934ed66acf45bf,

title = "Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity",

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 = "Humans, Canagliflozin/pharmacology, Diabetes Mellitus, Type 2/drug therapy, Autoimmunity, T-Lymphocytes, Sodium-Glucose Transporter 2 Inhibitors/therapeutic use, Autoimmune Diseases/drug therapy, Hypoglycemic Agents/pharmacology",

author = "Jenkins, {Benjamin J} and Julianna Blagih and Ponce-Garcia, {Fernando M} and Mary Canavan and Nancy Gudgeon and Simon Eastham and David Hill and Hanlon, {Megan M} and Ma, {Eric H} and Bishop, {Emma L} and April Rees and Cronin, {James G} and Jury, {Elizabeth C} and Dimeloe, {Sarah K} and Veale, {Douglas J} and Thornton, {Catherine A} and Vousden, {Karen H} and Finlay, {David K} and Ursula Fearon and Jones, {Gareth W} and Sinclair, {Linda V} and Vincent, {Emma E} and Nicholas Jones",

note = "Acknowledgments: We thank D.O.F. Skibinski, O. Bodger, A. Floudas, and S. Bain for useful discussion, A. Howden for proteomics advice, T. Jovic, E. Combellack, C. DeCourcey, K. Hawkins, and A. Tang for phlebotomy and all blood donors for their contribution to this work. B.J.J. is funded by a Swansea University Research Excellence Scholarship. G.W.J. is funded by a Versus Arthritis Career Development Fellowship (20305). J.B. was funded by a Canadian Institute for Health Research Postdoctoral Fellowship and the Kuok Family Postdoctoral Fellowship. E.E.V. is supported by a Diabetes UK RD Lawrence Fellowship (17/0005587) and by Cancer Research UK (C18281/A29019). This work was funded by a MRC New Investigator Research Grant (MR/X000095/1) awarded to N.J. We would like to acknowledge the FingerPrints Proteomics Facility at the University of Dundee, which is supported by the “Wellcome Trust Technology Platform” award (097945/B/11/Z). We thank the Metabolomics Facility at the Francis Crick Institute for their support. Copyright: {\textcopyright} 2023 The Author(s). Published by Elsevier Inc. ",

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doi = "10.1016/j.cmet.2023.05.001",

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Jenkins, BJ, Blagih, J, Ponce-Garcia, FM, Canavan, M, Gudgeon, N, Eastham, S, Hill, D, Hanlon, MM, Ma, EH, Bishop, EL, Rees, A, Cronin, JG, Jury, EC, Dimeloe, SK, Veale, DJ, Thornton, CA, Vousden, KH, Finlay, DK, Fearon, U, Jones, GW, Sinclair, LV, Vincent, EE & Jones, N 2023, 'Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity', Cell Metabolism, vol. 35, no. 7, pp. 1132-1146.e9. https://doi.org/10.1016/j.cmet.2023.05.001

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T1 - Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

AU - Jenkins, Benjamin J

AU - Blagih, Julianna

AU - Ponce-Garcia, Fernando M

AU - Canavan, Mary

AU - Gudgeon, Nancy

AU - Eastham, Simon

AU - Hill, David

AU - Hanlon, Megan M

AU - Ma, Eric H

AU - Bishop, Emma L

AU - Rees, April

AU - Cronin, James G

AU - Jury, Elizabeth C

AU - Dimeloe, Sarah K

AU - Veale, Douglas J

AU - Thornton, Catherine A

AU - Vousden, Karen H

AU - Finlay, David K

AU - Fearon, Ursula

AU - Jones, Gareth W

AU - Sinclair, Linda V

AU - Vincent, Emma E

AU - Jones, Nicholas

N1 - Acknowledgments: We thank D.O.F. Skibinski, O. Bodger, A. Floudas, and S. Bain for useful discussion, A. Howden for proteomics advice, T. Jovic, E. Combellack, C. DeCourcey, K. Hawkins, and A. Tang for phlebotomy and all blood donors for their contribution to this work. B.J.J. is funded by a Swansea University Research Excellence Scholarship. G.W.J. is funded by a Versus Arthritis Career Development Fellowship (20305). J.B. was funded by a Canadian Institute for Health Research Postdoctoral Fellowship and the Kuok Family Postdoctoral Fellowship. E.E.V. is supported by a Diabetes UK RD Lawrence Fellowship (17/0005587) and by Cancer Research UK (C18281/A29019). This work was funded by a MRC New Investigator Research Grant (MR/X000095/1) awarded to N.J. We would like to acknowledge the FingerPrints Proteomics Facility at the University of Dundee, which is supported by the “Wellcome Trust Technology Platform” award (097945/B/11/Z). We thank the Metabolomics Facility at the Francis Crick Institute for their support. Copyright: © 2023 The Author(s). Published by Elsevier Inc.

PY - 2023/7/11

Y1 - 2023/7/11

N2 - 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.

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KW - Humans

KW - Canagliflozin/pharmacology

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Autoimmunity

KW - T-Lymphocytes

KW - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use

KW - Autoimmune Diseases/drug therapy

KW - Hypoglycemic Agents/pharmacology

U2 - 10.1016/j.cmet.2023.05.001

DO - 10.1016/j.cmet.2023.05.001

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SN - 1550-4131

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SP - 1132-1146.e9

JO - Cell Metabolism

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