5,201,035 research outputs found

    Discovery

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    Introduction to Dendritic Cells: Discoveryhttps://digitalcommons.rockefeller.edu/introduction-dendritic-cells/1001/thumbnail.jp

    Introduction to Dendritic Cells

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    Introduction to Dendritic Cellshttps://digitalcommons.rockefeller.edu/introduction-dendritic-cells/1003/thumbnail.jp

    Maturation of Dendritic Cells

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    Introduction to Dendritic Cells: Maturatin of Dendritic Cellshttps://digitalcommons.rockefeller.edu/introduction-dendritic-cells/1005/thumbnail.jp

    Migration of Dendritic Cells

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    Introduction to Dendritic Cells: Migratin of Dendritic Cellshttps://digitalcommons.rockefeller.edu/introduction-dendritic-cells/1006/thumbnail.jp

    Dendritic Cell and Immune Tolerence

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    Introduction ot Dendritic Cells: Dendritic cell and immune tolerencehttps://digitalcommons.rockefeller.edu/introduction-dendritic-cells/1000/thumbnail.jp

    Transcriptional Regulator TonEBP Mediates Oxidative Damages in Ischemic Kidney Injury

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    TonEBP (tonicity-responsive enhancer binding protein) is a transcriptional regulator whose expression is elevated in response to various forms of stress including hyperglycemia, inflammation, and hypoxia. Here we investigated the role of TonEBP in acute kidney injury (AKI) using a line of TonEBP haplo-deficient mice subjected to bilateral renal ischemia followed by reperfusion (I/R). In the TonEBP haplo-deficient animals, induction of TonEBP, oxidative stress, inflammation, cell death, and functional injury in the kidney in response to I/R were all reduced. Analyses of renal transcriptome revealed that genes in several cellular pathways including peroxisome and mitochondrial inner membrane were suppressed in response to I/R, and the suppression was relieved in the TonEBP deficiency. Production of reactive oxygen species (ROS) and the cellular injury was reproduced in a renal epithelial cell line in response to hypoxia, ATP depletion, or hydrogen peroxide. The knockdown of TonEBP reduced ROS production and cellular injury in correlation with increased expression of the suppressed genes. The cellular injury was also blocked by inhibitors of necrosis. These results demonstrate that ischemic insult suppresses many genes involved in cellular metabolism leading to local oxidative stress by way of TonEBP induction. Thus, TonEBP is a promising target to prevent AKI

    Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL-Faslpr Mice

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    SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4-CD8- T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases

    PPM1A Controls Diabetic Gene Programming through Directly Dephosphorylating PPAR?? at Ser273

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    Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a master regulator of adipose tissue biology. In obesity, phosphorylation of PPAR gamma at Ser273 (pSer273) by cyclin-dependent kinase 5 (CDK5)/extracellular signal-regulated kinase (ERK) orchestrates diabetic gene reprogramming via dysregulation of specific gene expression. Although many recent studies have focused on the development of non-classical agonist drugs that inhibit the phosphorylation of PPAR gamma at Ser273, the molecular mechanism of PPAR gamma dephosphorylation at Ser273 is not well characterized. Here, we report that protein phosphatase Mg2+/Mn2+-dependent 1A (PPM1A) is a novel PPAR gamma phosphatase that directly dephosphorylates Ser273 and restores diabetic gene expression which is dysregulated by pSer273. The expression of PPM1A significantly decreases in two models of insulin resistance: diet-induced obese (DIO) mice and db/db mice, in which it negatively correlates with pSer273. Transcriptomic analysis using microarray and genotype-tissue expression (GTEx) data in humans shows positive correlations between PPM1A and most of the genes that are dysregulated by pSer273. These findings suggest that PPM1A dephosphorylates PPAR gamma at Ser273 and represents a potential target for the treatment of obesity-linked metabolic disorders
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