LXR nuclear receptors are transcriptional regulators of dendritic cell chemotaxis
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ABSTRACT:
PROVIDER: PRJNA430345 | ENA |
REPOSITORIES: ENA
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Project description:The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DC), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR-deficient mature DCs are defective in stimulus-induced migration in vitro and in vivo. Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished LXR-dependent induction of DC chemotaxis. Using the LDLR-/- mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for efficient emigration of DCs in response to chemotactic signals during inflammation.
2018-02-28 | GSE109284 | GEO
Project description:LXR signaling controls homeostatic dendritic cell maturation
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Project description:LXR signaling controls homeostatic dendritic cell maturation [BulkRNAseq]
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Project description:LXR signaling controls homeostatic dendritic cell maturation [scRNAseq]
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Project description:Dendritic cells (DCs) play a crucial role in the regulation of innate and adaptive immune responses. DCs initiate adaptive immune responses after their migration to secondary lymphoid organs, a process mainly driven by the expression of the chemokine receptor CCR7. LXR ligands/oxysterols released by tumors were shown to dampen DC migration to secondary lymphoid organs by the inhibition of CCR7 expression. We studied the gene expression modulation of DCs undergoing maturation (by LPS) in the presence of the oxysterol 22R-Hydroxycholesterol (22R-HC).
2019-02-27 | E-MTAB-6224 | biostudies-arrayexpress
Project description:Efferocytosis is critical for tissue homeostasis, as its deregulation is associated with several autoimmune pathologies. While engulfing apoptotic cells, phagocytes activate transcription factors, such as peroxisome proliferator-activated receptors (PPAR) or liver X receptors (LXR) that orchestrate metabolic, phagocytic, and inflammatory responses towards the ingested material. Coordination of these transcription factors in efferocytotic human macrophages (MF) is not fully understood. In this study, we evaluated the transcriptional profile of MF following the uptake of apoptotic Jurkat T cells using RNA-seq analysis. Results indicated upregulation of PPAR and LXR pathways but downregulation of sterol regulatory element-binding proteins (SREBP) target genes. Pharmacological inhibition and RNA interference pointed to LXR and PPARdelta as relevant transcriptional regulators, while PPARdelta did not substantially contribute to gene regulation. Mechanistically, lysosomal digestion and lysosomal acid lipase (LIPA) were required for PPAR and LXR activation, while PPARdelta activation also demanded an active lysosomal phospholipase A2 (PLA2G15). Pharmacological interference with LXR signaling attenuated ABCA1-dependent cholesterol efflux from efferocytotic MF, but suppression of inflammatory responses following efferocytosis occurred independently of LXR and PPARdelta. These data provide mechanistic details on LXR and PPARdelta activation in efferocytotic human MF.
2021-05-26 | GSE169160 | GEO
Project description:The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DCs), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR-deficient mature DCs are defective in stimulus-induced migration in vitro and in vivo Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished the LXR-dependent induction of DC chemotaxis. Using the low-density lipoprotein receptor-deficient (LDLR-/-) LDLR-/- mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for the efficient emigration of DCs in response to chemotactic signals during inflammation.
| S-EPMC5954201 | biostudies-literature
Project description:Transcriptional effects of LXR nuclear receptors on M-CSF-derived macrophages
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Project description:Transcriptional effects of LXR nuclear receptors on GM-CSF-derived macrophages
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Project description:The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice is dependent on LXR and correlates with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the role of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as PPAR signaling pathways, and subsequent ChIP-seq mapping of PPARM-NM-1 binding demonstrated binding of PPARM-NM-1 to 71-88% of the identified LXR:RXR binding sites. Sequence analysis of shared binding regions combined with sequential ChIP on selected sites indicate that LXR:RXR and PPARM-NM-1:RXR bind to degenerate response elements in a mutually exclusive manner. Together our findings suggest extensive and unexpected cross-talk between hepatic LXR and PPARM-NM-1 at the level of binding to shared genomic sites LXR, RXR, PPARalpha and RNA Polymerase II ChIP-seq on livers from female C57BL/6 wild-type and/or LXRM-NM-1/M-NM-2-deficient mice (13 weeks of age, n=1) treated by oral gavage once daily for 14 days with the RXR agonist bexarotene (100 mg/kg body weight [mpk], in 1% carboxymethylcellulose), the LXR agonist T0901317 (T09, 30 mpk) or vehicle alone.
2012-01-31 | E-GEOD-35262 | biostudies-arrayexpress