Jenkins, Benjamin J;
Blagih, Julianna;
Ponce-Garcia, Fernando M;
Canavan, Mary;
Gudgeon, Nancy;
Eastham, Simon;
Hill, David;
... Jones, Nicholas; + view all
(2023)
Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity.
Cell Metabolism
10.1016/j.cmet.2023.05.001.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.cmet.2023.05.001 |
| Publisher version: | https://doi.org/10.1016/j.cmet.2023.05.001 |
| Language: | English |
| Additional information: | © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | CD4 T cell, T cell, autoimmunity, canagliflozin, gliflozins, human, immunometabolism |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10171393 |
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