Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials

Sun, Fangfang; Geng, Shikai; Wang, Haiting; Wang, Huijing; Liu, Zhe; Wang, Xiaodong; Li, Ting; Wan, Weiguo; Lu, Liangjing; Teng, Xiangyu; Morel, Laurence; Ye, Shuang

doi:10.1136/lupus-2020-000429

Cited by 40 publications

(28 citation statements)

References 15 publications

(17 reference statements)

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“…This means that while the data may seem contradictory it is more likely that there is a complex feedback network regulating IFN signaling and mitochondrial oxidative stress in SLE. Along with the clinical progress of repurposing metabolic modulators, such as metformin, in the management of SLE [8, 32,33], our data may offer additional insight into the immunometabolism of SLE. Furthermore, attempts to predict the target genes of tRF-3009 (3'UTR region and promoter region) using miRNA prediction databases were a failure due to the lack of intersection between predicted target genes and transcriptome data (Supplementary Tables 4, 6, 7).…”

Section: Discussionmentioning

confidence: 93%

tRNA Derived Fragment (tRF)-3009 Modulates IFN-α-induced CD4+ T Cell Oxidative Phosphorylation in Lupus Patients

Geng

Wang

Xin

et al. 2021

Preprint

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Background Accumulating evidence suggests tRNA-derived fragments (tRFs) play important roles in cellular homeostasis. Here we aimed to explore aberrant expression of tRFs in CD4+ T cells from patients with systemic lupus erythematosus (SLE) and their potential function in SLE pathogenesis. Methods First, small RNA sequencing was performed on CD4+ T cells from four SLE patients and three healthy controls (HCs). Candidate tRFs were then validated in CD4+ T cells from 97 SLE patients and their relevant disease controls using qRT-PCR. Then sequencing was used to investigate the profiles of HC-derived CD4+ T cells transfected with tRF-3009. Lastly, tRF-3009 siRNA or tRF-3009 mimics were transfected into CD4+ T cells with/without IFN-α. Changes in oxygen consumption rate (OCR), ATP, and ROS production were analyzed. Results We identified 482 differentially expressed tRFs from SLE CD4+ T cells. With tRF-3009 identified for further analysis due to its upregulation and the positive correlations between its expression and SLEDAI, active lupus nephritis and serum IFN-α levels. In vitro, tRF-3009 over-expressing CD4+ T cell profiling and putative analysis linked this product to the type I IFN and oxidative phosphorylation (OXPHOS) pathways. Interestingly, IFN-α is capable of inducing ROS and ATP production in CD4+ T cells, while knockdown of tRF-3009 reversed this process. Overexpression of tRF-3009 in CD4+ T cells alone was sufficient to upregulate OCR, ROS, and ATP production. Conclusions Our study is the first to link aberrant tRF expression and SLE. tRF-3009 may serve as a metabolic modulator for IFN-α-induced CD4+ T cell OXPHOS in SLE.

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Section: Discussionmentioning

confidence: 93%

tRNA Derived Fragment (tRF)-3009 Modulates IFN-α-induced CD4+ T Cell Oxidative Phosphorylation in Lupus Patients

Geng

Wang

Xin

et al. 2021

Preprint

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“…In a separate study, metformin given alongside the glycolytic inhibitor 2-DG was shown to ameliorate autoimmune pathology in lupus-prone mice (134). A recent clinical trial into the efficacy of metformin in SLE patients found no efficacy in reducing the incidence of disease flares, although pooled analysis with a previous trial suggested a modest reduction in flare incidence was achieved, warranting further investigation (135,136).…”

Section: B Cell Metabolism and Autophagy As Therapeutic Targetsmentioning

confidence: 97%

B Cell Metabolism and Autophagy in Autoimmunity

Raza

Clarke

2021

Front. Immunol.

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B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies. During development and differentiation, B cells undergo drastic changes in their physiology. It is emerging that these are accompanied by equally significant shifts in metabolic phenotype, which may themselves also drive and enforce the functional properties of the cell. The dysfunction of B cells during autoimmunity is characterised by the breaching of tolerogenic checkpoints, and there is developing evidence that the metabolic state of B cells may contribute to this. Determining the metabolic phenotype of B cells in autoimmunity is an area of active study, and is important because intervention by metabolism-altering therapeutic approaches may represent an attractive treatment target.

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“…Metformin synergizes with 2-DG in the treatment of lupus mice (33) and has shown protective effects in some models of arthritis and Sjöegren syndrome (37)(38)(39), but these studies are focussed on acquired immunity. In humans, clinical trials have shown that metformin ameliorates SLE activity, at least in part by reducing neutrophil activation and plasmacytoid dendritic cell function (40,41).…”

Section: Manipulation Of Metabolic Pathwaysmentioning

confidence: 99%

Therapies Targeting Trained Immune Cells in Inflammatory and Autoimmune Diseases

Municio

Criado

2021

Front. Immunol.

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The concept of trained immunity has recently emerged as a mechanism contributing to several immune mediated inflammatory conditions. Trained immunity is defined by the immunological memory developed in innate immune cells after a primary non-specific stimulus that, in turn, promotes a heightened inflammatory response upon a secondary challenge. The most characteristic changes associated to this process involve the rewiring of cell metabolism and epigenetic reprogramming. Under physiological conditions, the role of trained immune cells ensures a prompt response. This action is limited by effective resolution of inflammation and tissue repair in order to restore homeostasis. However, unrestrained activation of innate immune cells contributes to the development of chronic inflammation and tissue destruction through the secretion of inflammatory cytokines, proteases and growth factors. Therefore, interventions aimed at reversing the changes induced by trained immunity provide potential therapeutic approaches to treat inflammatory and autoimmune diseases like rheumatoid arthritis (RA). We review cellular approaches that target metabolism and the epigenetic reprogramming of dendritic cells, macrophages, natural killer cells, and other trained cells in the context of autoimmune inflammatory diseases.

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Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials

Cited by 40 publications

References 15 publications

tRNA Derived Fragment (tRF)-3009 Modulates IFN-α-induced CD4+ T Cell Oxidative Phosphorylation in Lupus Patients

tRNA Derived Fragment (tRF)-3009 Modulates IFN-α-induced CD4+ T Cell Oxidative Phosphorylation in Lupus Patients

B Cell Metabolism and Autophagy in Autoimmunity

Therapies Targeting Trained Immune Cells in Inflammatory and Autoimmune Diseases

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