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LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux

ABSTRACT: LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux

PROVIDER: PRJNA432535 | ENA |

REPOSITORIES: ENA

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LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux [ATAC-Seq]

Project description:The activation of Liver X Receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying repressive activity of LXR are controversial and have been attributed to cholesterol efflux or to transrepression of Activator Protein-1 (AP-1) activity. Here, we find that cholesterol efflux contributes to LXR repression, while direct repressive functions of LXR also play a key role but are independent of AP-1. We use ATAC-seq to show that LXR reduces chromatin accessibility in cis at inflammatory gene enhancers containing LXR binding sites. Targets of this repressive activity are associated with leukocyte adhesion and neutrophil migration, and LXR agonist treatment suppresses neutrophil recruitment in a mouse model of sterile peritonitis. These studies suggest a model of repression in which liganded LXR binds in cis to canonical nuclear receptor binding sites and represses pro-atherogenic leukocyte functions in tandem with induction of LXR targets mediating cholesterol efflux.

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LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux [RNA-Seq]

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LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux [ATAC-Seq]

Project description:LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux [ATAC-Seq]

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LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux.

Project description: Not available

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IL-36/LXR axis modulates cholesterol metabolism and immune defense to Mycobacterium tuberculosis

Project description:Mycobacterium tuberculosis (Mtb) is a life-threatening pathogen in humans. Bacterial infection of macrophages usually triggers strong innate immune mechanisms, including IL-1 cytokine secretion. The newer member of the IL-1 family, IL-36, was recently shown to be involved in cellular defense against Mtb. To unveil the underlying mechanism of IL-36 induced antibacterial activity, we analyzed its role in the regulation of cholesterol metabolism, together with the involvement of Liver X Receptor (LXR) in this process. Here we report that, in Mtb-infected macrophages, IL-36 signaling modulates cholesterol biosynthesis and efflux via LXR. Moreover, IL-36 induces the expression of cholesterol-converting enzymes and the accumulation of LXR ligands, such as oxysterols. Ultimately, both IL-36 and LXR signaling play a role in the regulation of antimicrobial peptides expression and in Mtb growth restriction. These data provide novel evidence for the importance of IL‑36 and cholesterol metabolism mediated by LXR in cellular host defense against Mtb.

2018-02-14 | GSE103092 | GEO

LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux

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

2018-11-17 | GSE110002 | GEO

Epigenetic regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA

Project description:Nuclear receptors are important conduits between environmental cues and gene expression, but the molecular events governing spatial variation in their responses remain poorly understood. Here we outline an important role for a non-coding RNA in modulating the cell type-specific actions of the cholesterol-activated nuclear receptor LXR. LXR regulates the expression of genes involved in responses to excess cholesterol and has been causally linked to the pathogenesis and treatment of prevention and atherosclerosis in animals. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the critical cholesterol efflux gene Abca1. MeXis interacts with and guides the promoter binding of the nuclear receptor transcriptional coactivator DDX17. Loss of MeXis in murine immune cells has a marked impact on chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Our findings define MeXis as a lncRNA gatekeeper that modifies the actions of LXR in lipid-dependent control of macrophage gene expression. This has important implications for mechanisms that underlie spatial activation patterns of nuclear receptors. Our work opens a new gateway to targeting reverse cholesterol transport since it is conceivable that therapeutic approaches that enhance MeXis activity might reduce foam cell formation and atherogenesis.

2018-01-26 | GSE97207 | GEO

Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA

Project description:Nuclear receptors are important conduits between environmental cues and gene expression, but the molecular events governing spatial variation in their responses remain poorly understood. Here we outline an important role for a non-coding RNA in modulating the cell type-specific actions of the cholesterol-activated nuclear receptor LXR. LXR regulates the expression of genes involved in responses to excess cholesterol and has been causally linked to the pathogenesis and treatment of prevention and atherosclerosis in animals. We identify the lncRNA MeXis as an amplifier of LXRdependent transcription of the critical cholesterol efflux gene Abca1. MeXis interacts with and guides the promoter binding of the nuclear receptor transcriptional coactivator DDX17. Loss of MeXis in murine immune cells has a marked impact on chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Our findings define MeXis as a lncRNA gatekeeper that modifies the actions of LXR in lipid-dependent control of macrophage gene expression. This has important implications for mechanisms that underlie spatial activation patterns of nuclear receptors. Our work opens a new gateway to targeting reverse cholesterol transport since it is conceivable that therapeutic approaches that enhance MeXis activity might reduce foam cell formation and atherogenesis

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LXR signaling controls homeostatic dendritic cell maturation [BulkRNAseq]

Project description:Depending on how an antigen is perceived, dendritic cells (DCs) mature in an immunogenic or tolerogenic manner, safeguarding the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well characterized, the signals driving tolerogenic maturation in homeostasis are still poorly understood. Here we demonstrate that engulfment of apoptotic cells triggers homeostatic maturation of conventional cDC1s in the spleen. This process can be modeled by engulfment of empty, non-adjuvanted lipid nanoparticles (LNPs), is marked by intracellular accumulation of cholesterol, and highly unique to type 1 DCs. Engulfment of apoptotic cells or cholesterol-rich LNPs leads to activation of the LXR pathway driving cellular cholesterol efflux and repression of immunogenic genes. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs represses the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell immunity. These data demonstrate how DCs exploit the conserved cellular cholesterol efflux pathway to regulate induction of tolerance or immunity and reveal that administration of non-adjuvanted cholesterol-rich LNPs is a powerful platform for inducing tolerogenic DC maturation.

2023-03-30 | GSE228523 | GEO

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