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LXR nuclear receptors are transcriptional regulators of dendritic cell chemotaxis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE109284 | GEO | 2018/02/28

REPOSITORIES: GEO

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Project description:The objective of the study was to figure out the impact of LXR signaling on human macrophages. Primary human macrophages in an early differentiating and a mature differentiation state were treated with the LXR agonist T091317 for 4 and 24 h and transcriptome-wide expression analysis were performed. As LXRa is highly induced during macrophage differentiation and 68% of all LXRs targets change their expression during this process, we suggest that LXRs have essential functions in macrophage development. More than 238 genes are regulated in early as well as mature macrophages by activation of LXRs; most of them are up-regulated. LXRs administrate differentiation state specific as well as common macrophages functions related primarily to lipid homeostasis, immune response and cell fate. Interestingly, almost only genes related to lipid and cholesterol metabolism are overrepresented among early induced genes, whereas genes related to immune functions respond later, implying the existence of indirect mechanisms of control. Furthermore, in early differentiating macrophages cell proliferation and cell death associated genes are induced after 24 h of LXR activation, whereas in mature macrophages, showing high LXRa expression, the same functional cluster respond far earlier (4 h) after LXR ligand treatment. In conclusion, our data suggest that LXRs are modulators of macrophage differentiation, operating principally as positive transcriptional regulators of genes involved in lipid and cholesterol metabolism and by this indirectly influencing the immunophenotype of macrophages. CD14 positive cells of healthy donors were isolated by magnetic separation and differentiated in the presence of human serum to macrophages. At an early differentiating state (16 h after isolation) and at in mature differentiating state (day 11 after isolation) the cells were treated with the synthetical LXR agonist T091317 respective its solvent DMSO for 4 and 24 h. RNA was isolated and a whole genome microarray was performed.

Project description:Dendritic cells (DCs) are a complex group of cells which play a critical role in vertebrate immunity. Spleen or lymph node resident DCs are subdivided into conventional DC (cDC) subsets (CD11b and CD8alpha in mouse; BDCA1 and BDCA3 in man) and plasmacytoid DCs (pDCs). It is currently unclear if these various DC populations belong to a unique hematopoietic lineage and if the subsets identified in the mouse and human systems are evolutionary homologs. To bring novel insights into these questions, we sought conserved genetic signatures for these DCs through the analysis of a compendium of genome-wide expression profiles of mouse or human leukocytes. We show through clustering analysis that all spleen resident DC subsets form a distinct branch within the leukocyte family tree, and reveal a transcriptomal signature evolutionary conserved in all these DC subsets. Moreover we identify a large gene expression program shared between mouse and human plasmacytoid DCs, and smaller conserved profiles shared between mouse and human cDC subsets. Finally, we use compendium analysis to re-evaluate the classification of interferon-producing killer DCs (IKDCs) and lin-CD16+HLA-DR+ cells, which have both been claimed to be DCs, and show that these cells are more closely linked to NK or myeloid cells, respectively. Our study thus provides a unique resource for future investigation of the evolutionarily conserved molecular pathways governing the ontogeny and functions of leukocyte subsets, especially DCs. Experiment Overall Design: This study includes data from cell sort purified dendritic cells, B cells, NK cells, and CD8 T cells. 2 or 3 independent replicates were made for each cell type. The genearray was performed in an attempt to investigate the relationships between DCs subsets and with other leukocytes, in mouse, in human, and between these 2 species. To this end, public data for mouse CD4 T cells and macrophages, as well as public data for human leukocyte subsets were also used in the analysis. The results have led to the identification of specific transcriptional programs conserved between human and mouse dendritic cell subsets.

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LXR nuclear receptors are transcriptional regulators of dendritic cell chemotaxis

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