Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

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

doi:10.1016/j.cmet.2023.05.001

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Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Benjamin Jenkins, Julianna Blagih, Fernando Ponce Garcia

, 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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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...

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Published in:	Cell Metabolism
ISSN:	1550-4131 1932-7420
Published:	Elsevier BV 2023
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa63534
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first_indexed	2023-05-25T08:33:36Z
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spelling	v2 63534 2023-05-25 Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity 90f7cfd66781feba615436189178a528 Benjamin Jenkins Benjamin Jenkins true false 255a64f4bf43b5a1e83000de40e9f41c 0000-0003-0651-2704 Fernando Ponce Garcia Fernando Ponce Garcia true false ae088f7f8609d2b2ea4666f9b52b3c15 0000-0002-4408-634X April Rees April Rees true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false c71a7a4be7361094d046d312202bce0c 0000-0002-5153-573X Cathy Thornton Cathy Thornton true false 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false 2023-05-25 BMS 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. Journal Article Cell Metabolism 35 7 1132 1146.e9 Elsevier BV 1550-4131 1932-7420 Immunometabolism, T cell, CD4 T cell, gliflozins, canagliflozin, autoimmunity, human 11 7 2023 2023-07-11 10.1016/j.cmet.2023.05.001 http://dx.doi.org/10.1016/j.cmet.2023.05.001 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) MRC UKRI (MR/X000095/1) 2024-02-01T16:01:41.1272973 2023-05-25T09:31:20.3300903 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Benjamin Jenkins 1 Julianna Blagih 2 Fernando Ponce Garcia 0000-0003-0651-2704 3 Mary Canavan 4 Nancy Gudgeon 5 Simon Eastham 6 David Hill 7 Megan M. Hanlon 8 Eric H. Ma 9 Emma L. Bishop 10 April Rees 0000-0002-4408-634X 11 James Cronin 0000-0002-0590-9462 12 Elizabeth C. Jury 13 Sarah K. Dimeloe 14 Douglas J. Veale 15 Cathy Thornton 0000-0002-5153-573X 16 Karen H. Vousden 17 David K. Finlay 18 Ursula Fearon 19 Gareth W. Jones 20 Linda V. Sinclair 21 Emma E. Vincent 22 Nick Jones 0000-0003-4846-5117 23 63534__28119__4dd6510c40e349a4a4e03fc792edcdb6.pdf 63534.VOR.pdf 2023-07-13T15:37:25.4953625 Output 6535047 application/pdf Version of Record true © 2023 The Author(s). Published by Elsevier Inc. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title	Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity
spellingShingle	Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity Benjamin Jenkins Fernando Ponce Garcia April Rees James Cronin Cathy Thornton Nick Jones
title_short	Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity
title_full	Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity
title_fullStr	Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity
title_full_unstemmed	Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity
title_sort	Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity
author_id_str_mv	90f7cfd66781feba615436189178a528 255a64f4bf43b5a1e83000de40e9f41c ae088f7f8609d2b2ea4666f9b52b3c15 9cfd17551c0d1f7438895121e4fbb6e8 c71a7a4be7361094d046d312202bce0c 0fce0f7ddbdbfeb968f4e2f1e3f86744
author_id_fullname_str_mv	90f7cfd66781feba615436189178a528_*_Benjamin Jenkins 255a64f4bf43b5a1e83000de40e9f41c__Fernando Ponce Garcia ae088f7f8609d2b2ea4666f9b52b3c15__April Rees 9cfd17551c0d1f7438895121e4fbb6e8__James Cronin c71a7a4be7361094d046d312202bce0c__Cathy Thornton 0fce0f7ddbdbfeb968f4e2f1e3f86744_*_Nick Jones
author	Benjamin Jenkins Fernando Ponce Garcia April Rees James Cronin Cathy Thornton Nick Jones
author2	Benjamin Jenkins Julianna Blagih Fernando Ponce Garcia 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
format	Journal article
container_title	Cell Metabolism
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doi_str_mv	10.1016/j.cmet.2023.05.001
publisher	Elsevier BV
college_str	Faculty of Medicine, Health and Life Sciences
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description	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.
published_date	2023-07-11T16:01:42Z
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Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

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