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. Jones

Linda V. Sinclair, Emma E. Vincent, Nicholas Jones (Lead / Corresponding author)

Cell Signalling and Immunology

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

76 Citations (Scopus)

638 Downloads (Pure)

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
Number of pages	15
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

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

immunometabolism
T cell
CD4 T cell
gliflozins
canagliflozin
autoimmunity
human
CD4 T cell

ASJC Scopus subject areas

Molecular Biology
Physiology
Cell Biology

Access to Document

10.1016/j.cmet.2023.05.001Licence: CC BY

Final Published Version Final published version, 15.4 MBLicence: CC BY

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. https://doi.org/10.1016/j.cmet.2023.05.001

@article{159a39bdcffb46f2aa60c0c6cd3ed330,

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 = "immunometabolism, T cell, CD4 T cell, gliflozins, canagliflozin, autoimmunity, human, CD4 T cell",

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 = "Funding Information: 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). Copyright: {\textcopyright}2023 The Author(s)",

year = "2023",

month = jul,

day = "11",

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

language = "English",

volume = "35",

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journal = "Cell Metabolism",

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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. https://doi.org/10.1016/j.cmet.2023.05.001

TY - JOUR

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 - Funding Information: 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). Copyright: ©2023 The Author(s)

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.

AB - 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.

KW - immunometabolism

KW - T cell

KW - CD4 T cell

KW - gliflozins

KW - canagliflozin

KW - autoimmunity

KW - human

KW - CD4 T cell

UR - https://www.scopus.com/pages/publications/85163218491

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

EP - 1146

JO - Cell Metabolism

JF - Cell Metabolism

IS - 7

ER -

Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Strategic Award: Wellcome Trust Technology Platform

Fingerprints Proteomics Facility

Cite this

Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Strategic Award: Wellcome Trust Technology Platform

Equipment

Fingerprints Proteomics Facility

Cite this