Journal article 1036 views 254 downloads
Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity
,
Mary Canavan,
Nancy Gudgeon,
Simon Eastham,
David Hill,
Megan M. Hanlon,
Eric H. Ma,
Emma L. Bishop,
April Rees ,
James Cronin ,
Elizabeth C. Jury,
Sarah K. Dimeloe,
Douglas J. Veale,
Cathy Thornton ,
Karen H. Vousden,
David K. Finlay,
Ursula Fearon,
Gareth W. Jones,
Linda V. Sinclair,
Emma E. Vincent,
Nick Jones
Cell Metabolism, Volume: 35, Issue: 7, Pages: 1132 - 1146.e9
Swansea University Authors:
Benjamin Jenkins, Fernando Ponce Garcia , April Rees , James Cronin , Cathy Thornton , Nick Jones
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© 2023 The Author(s). Published by Elsevier Inc. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0).
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DOI (Published version): 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...
| Published in: | Cell Metabolism |
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| ISSN: | 1550-4131 1932-7420 |
| Published: |
Elsevier BV
2023
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa63534 |
| 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. |
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| Keywords: |
Immunometabolism, T cell, CD4 T cell, gliflozins, canagliflozin, autoimmunity, human |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
MRC UKRI (MR/X000095/1) |
| Issue: |
7 |
| Start Page: |
1132 |
| End Page: |
1146.e9 |