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Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity / BENJAMIN JENKINS

Swansea University Author: BENJAMIN JENKINS

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DOI (Published version): 10.23889/SUthesis.65366

Abstract

Autoimmune diseases are characterised by augmented T cell function, ultimately leading to chronic inflammation and tissue damage. Altered T cell function is supported by metabolic dysregulation in the setting of autoimmunity, therefore targeting immunometabolism by repurposing clinically approved me...

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Published: Swansea, Wales, UK 2023
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Jones, N. and Thornton, C. A.
URI: https://cronfa.swan.ac.uk/Record/cronfa65366
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spelling v2 65366 2023-12-21 Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity 6a7f90c8c28689cd139520e21e14ef08 BENJAMIN JENKINS BENJAMIN JENKINS true false 2023-12-21 Autoimmune diseases are characterised by augmented T cell function, ultimately leading to chronic inflammation and tissue damage. Altered T cell function is supported by metabolic dysregulation in the setting of autoimmunity, therefore targeting immunometabolism by repurposing clinically approved metabolic modulators, such as those used to treat type 2 diabetes (T2D), is an attractive prospect. Canagliflozin – a member of the newest class of T2D drugs, sodium glucose co-transporter 2 (SGLT2) inhibitors – has known off-target effects including inhibition of mitochondrial glutamate dehydrogenase (GDH) and complex I of the electron transport chain. Importantly, these properties are not shared with other SGLT2 inhibitors, particularly dapagliflozin which has very limited off-target effects. The effects of canagliflozin on human T cell function are unknown. This study revealed that canagliflozin, but not dapagliflozin, compromised the proliferation and effector function of human T cells. The inhibitory effect of canagliflozin was underpinned by reduced T cell activation. Proteomic analysis revealed that canagliflozin mediates changes on a global scale, inhibiting various aspects of T cell fitness including metabolism, mitochondrial function and protein translation. Specifically, MYC inhibition emerged as a predicted upstream regulator of the canagliflozin-induced changes in protein expression. Compromised cellular metabolism was confirmed in canagliflozin-treated CD4+ T cells, whereby oxidative phosphorylation and glycolysis were markedly impaired following inhibition of GDH and complex I. Mechanistically, canagliflozin inhibits early T cell receptor signalling, which subsequently impacted the downstream activity of signalling proteins including ERK, mTOR and MYC. Importantly, canagliflozin treatment of T cells derived from patients with autoimmune disorders – rheumatoid arthritis and systemic lupus erythematosus – significantly impaired their effector function. Again, these changes were underpinned by perturbed cellular metabolism and diminished activation. Together, this work provides a foundation for the repurposing of canagliflozin as a treatment for autoimmune disease. E-Thesis Swansea, Wales, UK Immunometabolism, T cell, CD4+ T cell, gliflozins, canagliflozin, autoimmunity, human 4 10 2023 2023-10-04 10.23889/SUthesis.65366 COLLEGE NANME COLLEGE CODE Swansea University Jones, N. and Thornton, C. A. Doctoral Ph.D Swansea University Research Excellence Scholarship (SURES) (PhD funding), Medical Research Council (MRC) (Project) Swansea University Research Excellence Scholarship (SURES) (PhD funding), Medical Research Council (MRC - MR/X000095/1) (Project). 2023-12-21T10:57:34.5979072 2023-12-21T10:43:29.6470710 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science BENJAMIN JENKINS 1 65366__29311__a7e868e90efe4eb3a6fb68ab0500305c.pdf 2023_Jenkins_BJ.final.65366.pdf 2023-12-21T10:50:58.8654773 Output 35770350 application/pdf E-Thesis – open access true Copyright: The Author, Benjamin J. Jenkins, 2023. Articles included in Appendices 8.1 - 8.4 distributed under the terms of a Creative Commons Attribution 4.0 International License (CC BY 4.0). true eng
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
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 6a7f90c8c28689cd139520e21e14ef08
author_id_fullname_str_mv 6a7f90c8c28689cd139520e21e14ef08_***_BENJAMIN JENKINS
author BENJAMIN JENKINS
author2 BENJAMIN JENKINS
format E-Thesis
publishDate 2023
institution Swansea University
doi_str_mv 10.23889/SUthesis.65366
college_str Faculty of Medicine, Health and Life Sciences
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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
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description Autoimmune diseases are characterised by augmented T cell function, ultimately leading to chronic inflammation and tissue damage. Altered T cell function is supported by metabolic dysregulation in the setting of autoimmunity, therefore targeting immunometabolism by repurposing clinically approved metabolic modulators, such as those used to treat type 2 diabetes (T2D), is an attractive prospect. Canagliflozin – a member of the newest class of T2D drugs, sodium glucose co-transporter 2 (SGLT2) inhibitors – has known off-target effects including inhibition of mitochondrial glutamate dehydrogenase (GDH) and complex I of the electron transport chain. Importantly, these properties are not shared with other SGLT2 inhibitors, particularly dapagliflozin which has very limited off-target effects. The effects of canagliflozin on human T cell function are unknown. This study revealed that canagliflozin, but not dapagliflozin, compromised the proliferation and effector function of human T cells. The inhibitory effect of canagliflozin was underpinned by reduced T cell activation. Proteomic analysis revealed that canagliflozin mediates changes on a global scale, inhibiting various aspects of T cell fitness including metabolism, mitochondrial function and protein translation. Specifically, MYC inhibition emerged as a predicted upstream regulator of the canagliflozin-induced changes in protein expression. Compromised cellular metabolism was confirmed in canagliflozin-treated CD4+ T cells, whereby oxidative phosphorylation and glycolysis were markedly impaired following inhibition of GDH and complex I. Mechanistically, canagliflozin inhibits early T cell receptor signalling, which subsequently impacted the downstream activity of signalling proteins including ERK, mTOR and MYC. Importantly, canagliflozin treatment of T cells derived from patients with autoimmune disorders – rheumatoid arthritis and systemic lupus erythematosus – significantly impaired their effector function. Again, these changes were underpinned by perturbed cellular metabolism and diminished activation. Together, this work provides a foundation for the repurposing of canagliflozin as a treatment for autoimmune disease.
published_date 2023-10-04T10:57:34Z
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