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Succinate facilities CD4+ T cell infiltration and CCL1 production to promote myofibroblast activation and obstruction-induced renal fibrosis

ABSTRACT: To understand the roles of succinate in CD4+ T cells, we performed RNA sequencing of isolated spleen CD4+ T cells treated with or without cell membrane permeable dimethyl succinate, which can enter into T cells and increase intracellular succinate concentration. The treatment led to upregulation of genes associated with T cell activation, including cell shape, inflammatory response, meiotic nuclear division, and leukocyte migration. These results suggest that succinate promotes CD4+ T cell activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE278379 | GEO | 2025/06/25

REPOSITORIES: GEO

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Succinate facilities CD4+ T cell infiltration and CCL1 production to promote myofibroblast activation and obstruction-induced renal fibrosis

Project description:Succinate facilities CD4+ T cell infiltration and CCL1 production to promote myofibroblast activation and obstruction-induced renal fibrosis

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Investigation of the effect of succinate and dimethyl malonate on murine bone-marrow derived macrophages (BMDMs) treated with or without LPS

Project description:We aim to further elucidate the effect of succinate and the succinate dehydrogenase inhibtor, dimethyl malonate, on macrophages treated with LPS. Specifically we want to deepen our understanding of how these reagents influence both LPS-induced IL-1B and IL-10.

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Myc-mediated SDHA Acetylation Triggers Epigenetic Regulation of Gene Expression and Tumorigenesis.

Project description:Trimethylated H3K4 (H3K4me3), which is often found surrounding the transcriptional start site of active genes, is strongly enriched in the promoter regions of Myc-targeted genes. Succinate, which inhibits JmjC domain-containing histone demethylases (JHDMs), can induce H3K4me3 level of the promoter regions. It's interesting to ask whether Myc can mediate H3K4me3 by regulating cellular succinate level. Here, We used ChIP-seq to study Myc modulates H3K4me3 by altering succinate levels, dimethyl succinate (DMS), a membrane-permeable succinate analog, was introduced to treat CA46 cells with high or depleted Myc expression. And we also performed RNA-seq assays in Myc expressed or depleted CA46 cells with or without DMS treatment.

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Project description:Trimethylated H3K4 (H3K4me3), which is often found surrounding the transcriptional start site of active genes, is strongly enriched in the promoter regions of Myc-targeted genes. Succinate, which inhibits JmjC domain-containing histone demethylases (JHDMs), can induce H3K4me3 level of the promoter regions. It's interesting to ask whether Myc can mediate H3K4me3 by inhibiting SDH activity and inducing cellular succinate level. Here, We used ChIP-seq to study Myc modulates H3K4me3 by altering succinate levels, dimethyl succinate (DMS), a membrane-permeable succinate analog, was introduced to treat P493-6 cells with high or depleted Myc expression. And we performed RNA-seq assays in Myc expressed or depleted P493-6 cells with or without DMS treatment. Besides, we also performed RNA-seq assays in Myc expressed or depleted P493-6 cells with or without 3-nitropropionic acid (3-NPA, SDH enzyme inhibitor) treatment.

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Interleukin 10 and succinate synergize to provide B cell help in human lupus

Project description:Autoantibodies against nucleic acids are a hallmark of Systemic Lupus Erythematosus. We recently uncovered that human oxidized DNA of mitochondrial origin released by activated lupus neutrophils represents a distinct class of interferogenic TLR9 ligand for plasmacytoid dendritic cells. We now show that oxidized mitochondrial DNA-activated plasmacytoid dendritic cells skew naïve CD4+ T cells towards IL2low, IFNγhigh, IL10high secreting B helper cells different from follicular helper and Type 1 regulatory CD4+ T cells. Furthermore, PD1-induced succinate and mitochondrial ROS accumulation revoke anergy, while IL10 and succinate synergize to deliver B cell help. We provide evidence that IL10-producing CD4+ T cells infiltrate the SLE kidney insterstitium, where they might play a role in extrafollicular B cell responses. Thus, we describe a novel B cell helper pathway that links innate and adaptive immunity alterations in human lupus.

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Project description:A better understanding of the molecular and cellular factors involved in human plasma cell differentiation will accelerate therapeutic target identification in autoantibody-mediated diseases such as Systemic Lupus Erythematosus (SLE). Here, we describe a novel CXCR3+ PD1hi CD4+ T cell ‘helper’ population expanded in blood and inflamed kidneys of SLE patients. Upon activation, these cells express IFNg and IL10 and display high levels of mitochondrial ROS (mtROS) as the result of reverse electron transfer (RET) fueled by succinate. Furthermore, T cell-derived succinate synergizes with IL10 to provide B cell help. Cells with similar phenotype and function are generated in vitro upon priming naive CD4+ T cells with oxidized mitochondrial DNA (Ox mtDNA)- activated plasmacytoid dendritic cells (pDCs) in a PD1-dependent manner. Our results provide a novel mechanism for the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

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Succinate diminishes biological activity and mitochondrial function of human adipose-derived stem cells

Project description:Alterations in succinate levels have been associated with various metabolic and inflammatory diseases. However, little is currently known about whether adipose-derived stem cells (ADSCs) undergo changes when exposed to succinate. Here, we investigate the biological properties, mitochondrial function and immunophenotype of ADSCs treated with succinate. We observed that reduced biological activity of ADSCs following by succinate stimulated. Of note, succinate treated-ADSCs exhibit mitochondrial dysfunctions, including increased mitochondrial fragments, decreased mitochondrial mass, increased ROS production, reduced Oxidative phosphorylation (OXPHOS). Furthermore, transcriptome analysis revealed that the downregulation of genes involved in cell proliferation, OXPHOS and metabolism, whereas the signaling pathways related to cancer, apoptosis, inflammation were upregulated upon succinate treatment. The findings indicate that ADSCs exposed to succinate exhibit signs of mitochondrial dysfunction, inflammation, and a significant decrease in biological activity.

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