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Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

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

Cell Metabolism, Volume: 35, Issue: 7, Pages: 1132 - 1146.e9

Swansea University Authors: Benjamin Jenkins, Fernando Ponce Garcia Orcid Logo, April Rees Orcid Logo, James Cronin Orcid Logo, Cathy Thornton Orcid Logo, Nick Jones Orcid Logo

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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
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URI: https://cronfa.swan.ac.uk/Record/cronfa63534
first_indexed 2023-05-25T08:33:36Z
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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.</abstract><type>Journal Article</type><journal>Cell Metabolism</journal><volume>35</volume><journalNumber>7</journalNumber><paginationStart>1132</paginationStart><paginationEnd>1146.e9</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1550-4131</issnPrint><issnElectronic>1932-7420</issnElectronic><keywords>Immunometabolism, T cell, CD4 T cell, gliflozins, canagliflozin, autoimmunity, human</keywords><publishedDay>11</publishedDay><publishedMonth>7</publishedMonth><publishedYear>2023</publishedYear><publishedDate>2023-07-11</publishedDate><doi>10.1016/j.cmet.2023.05.001</doi><url>http://dx.doi.org/10.1016/j.cmet.2023.05.001</url><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>External research funder(s) paid the OA fee (includes OA grants disbursed by the Library)</apcterm><funders>MRC UKRI (MR/X000095/1)</funders><projectreference/><lastEdited>2024-02-01T16:01:41.1272973</lastEdited><Created>2023-05-25T09:31:20.3300903</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Benjamin</firstname><surname>Jenkins</surname><order>1</order></author><author><firstname>Julianna</firstname><surname>Blagih</surname><order>2</order></author><author><firstname>Fernando</firstname><surname>Ponce Garcia</surname><orcid>0000-0003-0651-2704</orcid><order>3</order></author><author><firstname>Mary</firstname><surname>Canavan</surname><order>4</order></author><author><firstname>Nancy</firstname><surname>Gudgeon</surname><order>5</order></author><author><firstname>Simon</firstname><surname>Eastham</surname><order>6</order></author><author><firstname>David</firstname><surname>Hill</surname><order>7</order></author><author><firstname>Megan M.</firstname><surname>Hanlon</surname><order>8</order></author><author><firstname>Eric H.</firstname><surname>Ma</surname><order>9</order></author><author><firstname>Emma L.</firstname><surname>Bishop</surname><order>10</order></author><author><firstname>April</firstname><surname>Rees</surname><orcid>0000-0002-4408-634X</orcid><order>11</order></author><author><firstname>James</firstname><surname>Cronin</surname><orcid>0000-0002-0590-9462</orcid><order>12</order></author><author><firstname>Elizabeth C.</firstname><surname>Jury</surname><order>13</order></author><author><firstname>Sarah K.</firstname><surname>Dimeloe</surname><order>14</order></author><author><firstname>Douglas J.</firstname><surname>Veale</surname><order>15</order></author><author><firstname>Cathy</firstname><surname>Thornton</surname><orcid>0000-0002-5153-573X</orcid><order>16</order></author><author><firstname>Karen H.</firstname><surname>Vousden</surname><order>17</order></author><author><firstname>David K.</firstname><surname>Finlay</surname><order>18</order></author><author><firstname>Ursula</firstname><surname>Fearon</surname><order>19</order></author><author><firstname>Gareth W.</firstname><surname>Jones</surname><order>20</order></author><author><firstname>Linda V.</firstname><surname>Sinclair</surname><order>21</order></author><author><firstname>Emma E.</firstname><surname>Vincent</surname><order>22</order></author><author><firstname>Nick</firstname><surname>Jones</surname><orcid>0000-0003-4846-5117</orcid><order>23</order></author></authors><documents><document><filename>63534__28119__4dd6510c40e349a4a4e03fc792edcdb6.pdf</filename><originalFilename>63534.VOR.pdf</originalFilename><uploaded>2023-07-13T15:37:25.4953625</uploaded><type>Output</type><contentLength>6535047</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>&#xA9; 2023 The Author(s). 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spelling 2024-02-01T16:01:41.1272973 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 MEDS 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 Medical School COLLEGE CODE MEDS 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
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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
container_volume 35
container_issue 7
container_start_page 1132
publishDate 2023
institution Swansea University
issn 1550-4131
1932-7420
doi_str_mv 10.1016/j.cmet.2023.05.001
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
url http://dx.doi.org/10.1016/j.cmet.2023.05.001
document_store_str 1
active_str 0
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 2023-07-11T08:16:44Z
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score 11.047306

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