Liver X receptors regulate dendritic cell phenotype and function through blocked induction of the actin-bundling protein fascin.
Liver X receptors (LXRs) are nuclear receptors regulating lipid and cholesterol metabolism. Recent data revealed a cross talk between LXR and Toll-like receptor signaling in macrophages, indicating a role in immunity. Here, we show that LXRalpha is expressed in human myeloid dendritic cells (DCs) and induced during differentiation of monocyte-derived DCs, whereas LXRbeta is expressed constitutively at a very low level. LXR activation by 2 different LXR agonists strongly interfered with lipopolysaccharide (LPS)-induced but not with CD40L-induced DC maturation by altering DC morphology and suppressing interleukin-12-but enhancing interleukin-10-secretion. LXR activation in DCs largely blocked their T-cell stimulatory ability despite essentially unaltered expression of various antigen-presenting and costimulatory molecules. Immunologic synapse formation was significantly inhibited by LXR activation along with a complete block in LPS- but not CD40L-induced expression of the actin-bundling protein fascin. Notably, overexpression of fascin in LXR agonist-treated DCs restored immunologic synapse formation and restored their ability to activate T cells. In conclusion, our data reveal LXR as a potent modulator of DC maturation and function mediated in part by blocking the expression of fascin. Due to the central position of DCs in immunity, LXRalpha could be a potential novel target for immunomodulation.
Geyeregger
René
R
Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Medical University of Vienna, Austria.
Zeyda
Maximilian
M
Bauer
Wolfgang
W
Kriehuber
Ernst
E
Säemann
Marcus D
MD
Zlabinger
Gerhard J
GJ
Maurer
Dieter
D
Stulnig
Thomas M
TM
D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008840:Microfilament Proteins; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C020324:fascin