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Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228911 | GEO | 2023/04/04

REPOSITORIES: GEO

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Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Metabolic Pathways]

Project description:Augmented T-cell function leading to host damage in autoimmunity is supported by metabolic dysregulation. Targeting immunometabolism for the treatment of autoimmunity by repurposing clinically approved metabolic modulators, such as those used to treat people with type 2 diabetes (T2D), is therefore an attractive avenue. Canagliflozin, a class of the newest type of T2D drug – sodium glucose co-transporter 2 (SGLT2) inhibitors – has known off-target effects including mitochondrial glutamate dehydrogenase (GDH) and complex I inhibition. To date, the effects of SGLT2 inhibitors on human T-cell function are extremely limited. Here, we analysed 748 genes using the Nanostring nCounter® Metabolic Pathways Panel and discovered 38 genes that were differentially regulated between canagliflozin-treated (cana, C; n = 6) and DMSO vehicle control (V; n = 6) T-cells. Of these genes, 24 were downregulated, whilst 14 were upregulated. Notably, 17 of the 24 genes that were downregulated following canagliflozin treatment were associated with the cell cycle, whilst SMAD3 was the only cell cycle-associated gene upregulated by canagliflozin. These analyses allowed a greater understanding of the global changes in T-cell metabolism that occur in response to treatment with SGLT2 inhibitors.

2023-04-04 | GSE228910 | GEO

Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Autoimmune Profiling]

Project description:Augmented T-cell function leading to host damage in autoimmunity is supported by metabolic dysregulation. Targeting immunometabolism for the treatment of autoimmunity by repurposing clinically approved metabolic modulators, such as those used to treat people with type 2 diabetes (T2D), is therefore an attractive avenue. Canagliflozin, a class of the newest type of T2D drug – sodium glucose co-transporter 2 (SGLT2) inhibitors – has known off-target effects including mitochondrial glutamate dehydrogenase (GDH) and complex I inhibition. To date, the effects of SGLT2 inhibitors on human T-cell function are extremely limited. Here, we analysed 784 genes using the Nanostring nCounter® Autoimmune Profiling Panel and discovered 42 genes that were differentially regulated between canagliflozin-treated (cana, C; n = 6) and DMSO vehicle control (V; n = 6) T-cells. Of these genes, 39 were downregulated, including IL2, CSF2 and CCL20; whilst 3 were upregulated, including SELL. Dapagliflozin was used as another control, as this SGLT2 inhibitor does not exhibit any known off-target effects like canagliflozin. Here, there were no differentially expressed genes between dapagliflozin-treated (dapa, D; n = 4) and DMSO vehicle control (V; n = 4) T-cells. These analyses allowed a greater understanding of the global changes in T-cell function that occur in response to treatment with SGLT2 inhibitors.

2023-04-04 | GSE228909 | GEO

Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity.

Project description:Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity.

| PRJNA952139 | ENA

Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Metabolic Pathways]

Project description:Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Metabolic Pathways]

| PRJNA952145 | ENA

Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Autoimmune Profiling]

Project description:Canagliflozin impairs T-cell effector function via metabolic suppression in autoimmunity [Autoimmune Profiling]

| PRJNA952144 | ENA

Fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-09-16 | E-GEOD-71084 | biostudies-arrayexpress

Increased EZH2 function in regulatory T cells promotes their capacity to suppress autoimmunity by driving effector differentiation prior to activation.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-10 | GSE262131 | GEO

ADAM9 Up-regulates N-Cadherin via MiR-218 Suppression in Lung Adenocarcinoma Cells

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-07-03 | E-GEOD-52051 | biostudies-arrayexpress

Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-11-05 | GSE188322 | GEO

Histone Deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T Cells.

Project description:We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, and diverts Vα14/Jα18 TCR transgenic thymocytes into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice mitigated their disease, suggesting that the combined defects in negative selection and iNKT cells due to altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.

| S-EPMC5943034 | biostudies-literature

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