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TLR-dependent transcriptional reprogramming of LXRα cistrome in bone marrow-derived macrophages

ABSTRACT: The Liver X receptors (LXRα and LXRβ) are members of the nuclear receptor superfamily of transcription factors, and play key roles in the coordination of both metabolic and immune responses in macrophages. Both LXRs are expressed in macrophages and they share a high degree of sequence homology but their individual roles in different models of macrophage cultures, particularly in response to inflammation, have not been characterized. Previous studies have shown that ligand pre-treated LXRs repress the induction of pro-inflammatory cytokines in macrophages. Here, we show evidence that the expression of LXRα (but not LXRβ) is transcriptionally regulated at late phases of an LPS-induced inflammatory response in bone marrow-derived macrophages (BMDMs). Regulation of LXRα expression is controlled at the transcriptional levels by inflammatory signaling networks. Transcriptional profiling studies and ChIP-seq data identified a number of innate immune pathways whose expression is substantially controlled by LXRα in BMDMs. In summary, our data shows that LXRα plays a previously unrecognized role in innate immunity by transcriptional regulation of a battery of inflammatory genes through TLR and Type-I IFN-dependent signaling in macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE200922 | GEO | 2022/12/31

REPOSITORIES: GEO

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TLR-dependent transcriptional reprogramming of LXRα cistrome in bone marrow-derived macrophages

Project description:The Liver X receptors (LXRα and LXRβ) are members of the nuclear receptor superfamily of transcription factors, and play key roles in the coordination of both metabolic and immune responses in macrophages. Both LXRs are expressed in macrophages and they share a high degree of sequence homology but their individual roles in different models of macrophage cultures, particularly in response to inflammation, have not been characterized. Previous studies have shown that ligand pre-treated LXRs repress the induction of pro-inflammatory cytokines in macrophages. Here, we show evidence that the expression of LXRα (but not LXRβ) is transcriptionally regulated at late phases of an LPS-induced inflammatory response in bone marrow-derived macrophages (BMDMs). Regulation of LXRα expression is controlled at the transcriptional levels by inflammatory signaling networks. Transcriptional profiling studies and ChIP-seq data identified a number of innate immune pathways whose expression is substantially controlled by LXRα in BMDMs. In summary, our data shows that LXRα plays a previously unrecognized role in innate immunity by transcriptional regulation of a battery of inflammatory genes through TLR and Type-I IFN-dependent signaling in macrophages.

2020-05-01 | GSE130586 | GEO

TLR-dependent transcriptional reprogramming of LXRα cistrome in bone marrow-derived macrophages [RNA-seq]

2024-04-02 | GSE254257 | GEO

Common and differential transcriptional actions of LXRalpha and LXRbeta in murine macrophages

Project description:The LXR proteins, LXRα and LXRβ, are transcription factors that belong to the nuclear receptor superfamily. LXRs are activated by oxysterols and control the transcription of genes involved in the regulation of cholesterol and fatty acid metabolism. They also mediate several aspects of macrophage biology, including inflammatory responses, cell survival in response to infection and phagocytosis of apoptotic cells. LXRs share a high degree of sequence homology and most of their functions are believed to be performed similarly by LXRα and LXRβ. However, the individual, transcriptional roles of each LXR isoform have not been characterized in detail, in part due to the lack of specific experimental tools that can discriminate between LXRα and LXRβ actions. To identify common and differential transcriptional functions of LXR nuclear receptors in macrophages, we developed a cellular model of stable expression of FLAG-tagged LXRα or LXRβ in LXR-null immortalized murine bone marrow-derived macrophages (parental line published Elife. 2015 Jul 14;4:e08009. doi: 10.7554/eLife.08009). To take a deeper insight into the epigenomic features of LXR nuclear receptors, we performed chromatin immunoprecipitation coupled to next-generation sequencing (ChIP-seq) to identify genome-wide binding locations of LXRα and LXRβ in the presence of a synthetic agonist (GW3965, 1uM). Additionally, we identified genome-wide DNA locations of acetylation mark on lysine 27 of histone H3 (H3K27ac), upon LXR agonist (GW3965, 1uM) and antagonist (GW2033, 1uM) treatment. Collectively, these studies will increase our understanding of common and differential genomic actions of LXRα and LXRβ in cultured murine macrophages.

2017-10-19 | GSE104027 | GEO

Foam cell specific LXRα ligand

Project description:OBJECTIVE: The liver X receptor α (LXRα) is a ligand-dependent nuclear receptor and the major regulator of reverse cholesterol transport in macrophages. This makes it an interesting target for mechanistic study and treatment of atherosclerosis. METHODS AND RESULTS: We optimized a promising stilbenoid structure (STX4) in order to reach nanomolar effective concentrations in LXRα reporter-gene assays. STX4 displayed the unique property to activate LXRα effectively but not its subtype LXRβ. The potential of STX4 to increase transcriptional activity as an LXRα ligand was tested with gene expression analyses in THP1-derived human macrophages and oxLDL-loaded human foam cells. Only in foam cells but not in macrophage cells STX4 treatment showed athero-protective effects with similar potency as the synthetic LXR ligand T0901317 (T09). Surprisingly, combinatorial treatment with STX4 and T09 resulted in an additive effect on reporter-gene activation and target gene expression. In physiological tests the cellular content of total and esterified cholesterol was significantly reduced by STX4 without the undesirable increase in triglyceride levels as observed for T09. CONCLUSIONS: STX4 is a new LXRα-ligand to study transcriptional regulation of anti-atherogenic processes in cell or ex vivo models, and provides a promising lead structure for pharmaceutical development.

2013-09-05 | GSE39079 | GEO

Liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRα and LXRβ subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRα and LXRβ knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRα KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRβ KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRα KO mice, but not LXRβ KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRβ in skeletal muscle.

2010-03-31 | GSE13192 | GEO

TLR-dependent transcriptional reprogramming of LXRα cistrome in bone marrow-derived macrophages

Project description:TLR-dependent transcriptional reprogramming of LXRα cistrome in bone marrow-derived macrophages

| PRJNA540686 | ENA

Next Generation Sequencing of LdlrKO LXRα-phosphorylation disrupted macrophage transcriptomes

Project description:Liver X Receptors (LXRα and β) are ligand-activated transcription factors that play a key role in the control of lipid homeostasis, as well as modulation of immunity and inflammation. Besides ligand binding, LXR activity can be regulated by posttranslational modifications, such as phosphorylation. This study aims to assess changes in bone marrow derived macrophage transcriptional profiles of mice that carry LysMcre directed phosphorylation deficient-version of LXRα compared (S196A) to wild-type (WT).

2018-06-29 | GSE112213 | GEO

Integrated transcriptomic and metabolomic analysis reveals the metabolic programming of GM-CSF-and M-CSF-differentiated mouse macrophages

Project description:Macrophages play a critical role in the inflammatory response and tumor development. Macrophages are primarily divided into pro-inflammatory M1-like and anti-inflammatory M2-like macrophages based on their activation status and functions. In vitro macrophage models could be derived from mouse bone marrow cells stimulated with two types of differentiation factors: GM-CSF (GM-BMDMs) and M-CSF (M-BMDMs), to represent M1-and M2-like macrophages, respectively. Since macrophage differentiation requires coordinated metabolic reprogramming and transcriptional rewiring in order to fulfill their distinct roles, we combined both transcriptome and metabolome analysis, coupled with experimental validation, to gain insight into the metabolic status of GM-and M-BMDMs. The data revealed higher levels of the tricarboxylic acid cycle (TCA cycle), oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and urea and ornithine production from arginine in GM-BMDMs, and a preference for glycolysis, fatty acid storage, bile acid metabolism, and citrulline and nitric oxide (NO) production from arginine in M-BMDMs. Correlation analysis with the proteomic data showed high consistency in the mRNA and protein levels of metabolic genes. Similar results were also obtained when compared to RNA-seq data of human monocyte derived macrophages from the GEO database. Furthermore, canonical macrophage functions such as inflammatory response and phagocytosis were tightly associated with the representative metabolic pathways. In the current study, we identified the core metabolites, metabolic genes, and functional terms of the two distinct mouse macrophage populations. We also distinguished the metabolic influences of the differentiation factors GM-CSF and M-CSF, and wish to provide valuable information for in vitro macrophage studies.

2023-09-19 | MTBLS6502 | MetaboLights

NR1H3 (LXRα) IS ASSOCIATED WITH PRO-INFLAMMATORY MACROPHAGES, PREDICTS SURVIVAL AND PROVIDES RATIONALE FOR NEW IMMUNOMODULATION IN DIFFUSE LARGE B-CELL LYMPHOMA

Project description:The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for potential prognostic and therapeutic purposes. By comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor in M1-like pro-inflammatory Mo. By determining an expression cut-off of NR1H3, we used digital-expression to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3high patients displayed longer survival compared to NR1H3low cases and, a high-resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Finally, treating in vitro generated M2 Mo, that display basal low NR1H3, with a new oral LXR agonist, we observed significant upregulation of NR1H3 along with inflammatory genes. Overall, our findings indicate NR1H3 as a biomarker of Mo in DLBCL, useful to identify patients at different risk and heterogenous TME who could benefit from Mo-directed immunomodulation in DLBCL. Expression data from in vitro generated macrophages from ThP1 treated either with DMSO or RGX104

2022-05-31 | GSE195651 | GEO

CTRP6 promotes macrophage inflammatory response and its deficiency attenuates LPS-induced inflammation

Project description:Macrophages play critical roles in inflammation and tissue homeostasis, and their functions are regulated by various autocrine, paracrine, and endocrine factors. We have previously shown that CTRP6, a secreted protein of the C1q family, targets both adipocytes and macrophages to promote obesity-linked inflammation in adipose tissue. However, the gene programs and signaling pathways directly regulated by CTRP6 in macrophage remain unknown. Here, we combine transcriptomic and phosphoproteomic analyses to show that CTRP6 activates inflammatory gene programs and signaling pathways in bone marrow-derived macrophages (BMDMs). Treatment of BMDMs with CTRP6 upregulates proinflammatory, and suppresses the anti-inflammatory, gene expression. We show that CTRP6 activates p44/42-MAPK, p38-MAPK, and NF-κB signalings to promote inflammatory cytokine secretion from BMDMs, and that pharmacologic inhibition of these signaling pathways largely abolish the effects of CTRP6. Pretreatment of BMDMs with CTRP6 further augments LPS-induced inflammatory signaling and cytokine secretion from BMDMs. Consistent with the metabolic phenotype of proinflammatory M1-like macrophages, CTRP6 treatment induces a shift toward aerobic glycolysis and lactate production, reduces oxidative metabolism, and elevates mitochondrial ROS production in BMDMs. We use a Ctrp6 knockout mouse model to further confirm the physiologic relevance of our in vitro findings. BMDMs from CTRP6-deficient mice are less inflammatory at baseline and show a marked suppression of LPS-induced inflammatory gene expression and cytokine secretion. Loss of CTRP6 in mice also dampens LPS-induced inflammation and hypothermia. Collectively, we provide mechanistic evidence that CTRP6 regulates macrophage function, and neutralizing CTRP6 activity may have beneficial effects in reducing inflammation.

2024-01-26 | PXD042268 | Pride

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