E-Thesis 84 views 28 downloads
Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity / BENJAMIN JENKINS
Swansea University Author: BENJAMIN JENKINS
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PDF | E-Thesis – open access
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).
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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...
| Published: |
Swansea, Wales, UK
2023
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| 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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| 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 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. |
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| Keywords: |
Immunometabolism, T cell, CD4+ T cell, gliflozins, canagliflozin, autoimmunity, human |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
Swansea University Research Excellence Scholarship (SURES) (PhD funding), Medical Research Council (MRC - MR/X000095/1) (Project). |