Canagliflozin Impairs T-Cell Effector Function via Metabolic Suppression in Autoimmunity

Jenkins, Benjamin; Blagih, Julianna; Eastham, Simon; Hill, David; Ponce-Garcia, Fernando M.; Hanlon, Megan; Ma, Eric; Bishop, Emma; Bull, Caroline J.; Rees, April; Cronin, James G.; Jury, Elizabeth C.; Dimeloe, Sarah; Veale, Douglas; Thornton, Catherine A.; Vousden, Karen H.; Finlay, David K.; Fearon, Ursula; Sinclair, Linda V.; Jones, Gareth Wyn; Vincent, Emma E.; Jones, Nick

doi:10.2139/ssrn.4187261

Cited by 7 publications

(9 citation statements)

References 56 publications

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“…In summary, we found that genetic ablation of SGLT2 exerted more profound effects than pharmacological inhibition. Our data overall confirm previous studies reporting an effect of SGLT2 inhibition on cytokine secretion (45–47), which may be attributed to a number of mechanisms such as macrophage polarisation (9), T-cell suppression (8) or resolution of low-grade inflammation through glycosuria (23). However, SGLT2 null mice demonstrated a significantly improved metabolic phenotype, compared to SGLT2 inhibitor-treated mice.…”

Section: Discussionsupporting

confidence: 91%

“…Despite their beneficial effects, their exact mechanisms of action are not fully understood, and may extend beyond renal glucose reabsorption. In particular, there is growing evidence for a broader, pleiotropic effect of SGLT2 inhibitors on immune regulation (6, 7), including inhibition of T-cell activation and proliferation (8) as well as modulation of macrophage M2 polarization (9). These findings hint at an intriguing immunometabolic role for SGLT2.…”

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confidence: 99%

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Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels

Brisnovali,

Franco,

Abdelgawwad

et al. 2024

Preprint

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Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing Type 2 Diabetes (T2D). Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high fat diet-fed control, chronically dapagliflozin-treated mice and total-body SGLT2/Slc5a2 knockout mice. SGLT2 null mice exhibited superior glucose tolerance and insulin sensitivity compared to control or dapagliflozin-treated mice, independent of glycosuria and body weight. Moreover, SGLT2 null mice demonstrated physiological regulation of corticosterone secretion, with lowered morning levels compared to control mice. Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly interleukin 6 (IL-6). Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 increased SGLT2 expression in kidney HK2 cells suggesting a role for cytokines in the effects of hyperglycemia. Collectively, our study elucidates a potential interplay between SGLT2 activity, immune modulation, and metabolic homeostasis.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels

Brisnovali,

Franco,

Abdelgawwad

et al. 2024

Preprint

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“…Intriguingly, canagliflozin has been shown to modulate T cell function in vitro via multiple mechanisms, including by inhibiting T cell receptor signaling [27 ▪ ]. This extended to CD4 + T cells from cohorts of patient with systemic lupus erythematosus (SLE) and rheumatoid arthritis.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Sodium-glucose cotransporter 2 inhibitors: are they ready for prime time in the management of lupus nephritis?

Wagner,

Rao

2024

Current Opinion in Rheumatology

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Purpose of review Lupus nephritis is a common complication of systemic lupus erythematosus and is associated with significant morbidity and mortality. The utility of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the management of lupus nephritis is currently uncertain. Here, we summarize the rationale for their use among patient with lupus nephritis. Recent findings SGLT2 inhibitors were initially developed as antihyperglycemic agents. They have since been shown to have additional, profound effects to slow the progression of chronic kidney disease and lessen the long-term risks of cardiovascular disease in large clinic trials of patients with chronic kidney disease, with and without diabetes, as well as in patients with and without proteinuria. Patients with recent exposure to immunosuppression were excluded from these trials due to concern for risk of infection. In the few, small trials of patients with lupus nephritis, SGLT2 inhibitors were found to be well tolerated. They have been shown to reduce proteinuria and to have modest beneficial effects on blood pressure and BMI among patients with lupus nephritis. They have not been shown to influence disease activity. Summary SGLT2 inhibitors may have a role in mitigating the chronic renal and cardiovascular effects of lupus nephritis. They should be introduced after kidney function has been stabilized with appropriate immunosuppression, in conjunction with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. They currently have no role in active disease.

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“…Proteomics analysis was done as previously described 56 . CD8 hi and CD8 lo or MitoSnap+ and MitoSnapdaughter-cells following naïve CD8 + T cell activation were purified by FACS.…”

Section: Proteomicsmentioning

confidence: 99%

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy

Borsa,

Lechuga-Vieco,

Kayvanjoo

et al. 2024

Preprint

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T cell immunity is impaired during ageing, particularly in memory responses needed for efficient vaccination. Autophagy and asymmetric cell division (ACD) are cell biological mechanisms key to memory formation, which undergo a decline upon ageing. However, despite the fundamental importance of these processes in cellular function, the link between ACD and in vivo fate decisions has remained highly correlative in T cells and in the field of mammalian ACD overall. Here we provide robust causal evidence linking ACD to in vivo T cell fate decisions and our data are consistent with the concept that initiation of asymmetric T cell fates is regulated by autophagy. Analysing the proteome of first-daughter CD8+T cells following TCR-triggered activation, we reveal that mitochondrial proteins rely on autophagy for their asymmetric inheritance and that damaged mitochondria are polarized upon first division. These results led us to evaluate whether mitochondria were asymmetrically inherited and to functionally address their impact on T cell fate. For this we used a novel mouse model that allows sequential tagging of mitochondria in mother and daughter cells, enabling their isolation and subsequent in vivo analysis of CD8+T cell progenies based on pre-mitotic cell cargo. Autophagy-deficient CD8+T cells showed impaired clearance and symmetric inheritance of old mitochondria, suggesting that degradation events promote asymmetry and are needed to generate T cells devoid of old organelles. Daughter cells inheriting old mitochondria are more glycolytic and upon adoptive transfer show reduced memory potential, whereas daughter cells that have not inherited old mitochondria from the mother cell are long-lived and expand upon cognate-antigen challenge. Proteomic and single-cell transcriptomic analysis of cells inheriting aged mitochondria suggest that their early fate divergence relies on one carbon metabolism as a consequence of poor mitochondrial quality and function. These findings increase our understanding of how T cell diversity is early-imprinted during division and will help foster the development of strategies to modulate T cell function.

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Canagliflozin Impairs T-Cell Effector Function via Metabolic Suppression in Autoimmunity

Cited by 7 publications

References 56 publications

Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels

Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels

Sodium-glucose cotransporter 2 inhibitors: are they ready for prime time in the management of lupus nephritis?

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy

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Canagliflozin Impairs T-Cell Effector Function via Metabolic Suppression in Autoimmunity

Cited by 7 publications

References 56 publications

Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels

Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels

Sodium-glucose cotransporter 2 inhibitors: are they ready for prime time in the management of lupus nephritis?

Inheritance of old mitochondria controls early CD8+T cell fate commitment and is regulated by autophagy

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Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy