Liver X receptors regulate dendritic cell phenotype and function through blocked induction of the actin-bundling protein fascin

Geyeregger R, Zeyda M, Bauer W, Kriehuber E, Saemann MD, Zlabinger GJ, Maurer D, Stulnig TM
Source: Blood
Publication Date: (2007)
Issue: 109(10): 4288-95
Research Area:
Immunotherapy / Hematology
Cells used in publication:
Dendritic cell (NHDC), human
Species: human
Tissue Origin: blood
Nucleofector® I/II/2b
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.