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Nuclear receptor Nur77 regulates immunomechanics of macrophages

ABSTRACT: Nuclear receptor Nur77 regulates immunomechanics of macrophages

PROVIDER: PRJNA1065503 | ENA |

REPOSITORIES: ENA

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Nuclear receptor Nur77 regulates immunomechanics of macrophages

Project description:Macrophages exhibit remarkable plasticity in their morphology and mechanics, enabling them to adapt and execute essential inflammatory functions, such as navigating through inflamed tissue and pathogen engulfment. However, the precise regulatory mechanisms governing these dynamic changes in macrophage mechanics during inflammation remain poorly understood. Although the involvement of nuclear receptor Nur77 in macrophage inflammation has been extensively investigated, its potential correlation with cellular mechanics has not been investigated. In this study, we employ cytoskeletal imaging, single-cell acoustic force spectroscopy (AFS), migration and phagocytosis experiments, and RNA-sequencing analysis on bone marrow-derived macrophages (BMDMs) to compare wild-type (WT) and Nur77-deficient (Nur77-KO) cells. Our findings reveal that Nur77-KO BMDMs exhibit changes to their actin networks compared to WT BMDMs, which is associated with a stiffer and more rigid phenotype. Subsequent in-vitro experiments validated our observations, showcasing that Nur77 deficiency leads to enhanced migration, reduced adhesion, and increased phagocytic activity. The transcriptomics data confirmed altered mechanics-related pathways in Nur77-deficient macrophage that are accompanied by a robust pro-inflammatory phenotype. Utilizing previously obtained ChIP-data, we revealed that Nur77 directly targets differentially expressed genes associated with cellular mechanics. In conclusion, while Nur77 is recognized for its role in reducing inflammation of macrophages by inhibiting the expression of pro-inflammatory genes, our study identifies a novel regulatory mechanism where Nur77 governs macrophage inflammation through the modulation of expression of genes involved in cellular mechanics.

2024-08-02 | GSE253423 | GEO

Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages [RNA-seq]

Project description:Mitochondrial biogenesis requires precise regulation of both mitochondrial-encoded and nuclear-encoded genes. Nuclear receptor Nur77 is known to regulate mitochondrial metabolism in macrophages and skeletal muscle cells. Here, we compared genome-wide Nur77 binding site and target gene expression in these two cell types, which revealed conserved roles for this nuclear receptor in the regulation of nuclear-encoded mitochondrial ribosomal proteins (MRP) and enrichment of motifs for the transcription factor Yin-Yang 1 (YY1). We show that Nur77 and YY1 interact, that YY1 increases Nur77 activity, and that their binding sites are co-enriched at MRP gene loci. Nur77 and YY1 co-expression synergistically increases mitochondrial abundance and activity in macrophages but not skeletal muscle. As such, we identify a macrophage-specific Nur77-YY1 interaction that enhances mitochondrial metabolism.

2024-05-07 | GSE263316 | GEO

Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages [ChIP-seq]

2024-05-07 | GSE263315 | GEO

Nuclear receptor Nur77 limits the macrophage inflammatory response by reprogramming mitochondrial metabolism (RNA-seq)

Project description:Activation of macrophages by inflammatory stimuli leads to reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines. Hallmarks of this metabolic rewiring are downregulation of α-ketoglutarate formation via isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the nuclear receptor Nur77 (Nr4a1) as a key regulator of the pro-inflammatory metabolic switch in macrophages. Nur77-deficient macrophages fail to downregulate IDH expression and accumulate higher levels of succinate and other downstream TCA cycle metabolites in response to an inflammatory stimulus. Consequently, these macrophages produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis development and leads to increased systemic succinate levels. In conclusion, Nur77 supports an anti-inflammatory metabolic state in macrophages that protects against chronic inflammatory diseases such as atherosclerosis.

2018-08-21 | GSE102359 | GEO

Nuclear receptor Nur77 limits the macrophage inflammatory response by reprogramming mitochondrial metabolism (ChIP-seq)

2018-08-21 | GSE102393 | GEO

Nur77-deficiency in bone marrow-derived macrophages modulates inflammatory responses, extracellular matrix homeostasis, phagocytosis and tolerance

Project description:The nuclear orphan receptor Nur77 (NR4A1, TR3, or NGFI-B) has been shown to exhibit an anti-inflammatory function in macrophages. To further elucidate the role of Nur77 in macrophage physiology, we compared the transcriptome of bone marrow-derived macrophages (BMM) from wild-type (WT) and Nur77-knockout (KO) mice both before and after stimulation with IL4 or LPS. Comparison of gene expression in bone marrow-derived macrophages, isolated from 3 wild-type (control) and 3 Nur77-/- mice (case), left untreated or stimulated in triplicate for 8 hours with LPS or IL-4

2016-03-01 | E-GEOD-68167 | biostudies-arrayexpress

Nur77-deficiency in bone marrow-derived macrophages modulates inflammatory responses, extracellular matrix homeostasis, phagocytosis and tolerance

2016-03-01 | GSE68167 | GEO

Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages.

Project description:Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages.

| PRJNA1096690 | ENA

Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages [RNA-seq]

Project description:Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages [RNA-seq]

| PRJNA1096697 | ENA

Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages [ChIP-seq]

Project description:Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages [ChIP-seq]

| PRJNA1096698 | ENA