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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4288-4295.
Prepublished online as a Blood First Edition Paper on January 25, 2007; DOI 10.1182/blood-2006-08-043422.
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Submitted August 31, 2006
Accepted January 18, 2007
Liver X receptors regulate dendritic cell phenotype and function through blocked induction of the actin bundling protein fascin
Rene Geyeregger, Maximilian Zeyda, Wolfgang Bauer, Ernst Kriehuber, Marcus D Saemann, Gerhard J Zlabinger, Dieter Maurer, and Thomas M Stulnig*
Dept of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria
Dept of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
Institute of Immunology, Medical University of Vienna, Vienna, Austria
CeMM-Center of Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
* Corresponding author; email: thomas.stulnig{at}meduniwien.ac.at.
Liver X receptors (LXR) are nuclear receptors regulating lipid and cholesterol metabolism. Recent data revealed a crosstalk between LXR and Toll-like receptor signaling in macrophages, indicating a role in immunity. Here, we show that LXR is expressed in human myeloid dendritic cells (DC) and induced during differentiation of monocyte-derived DC, whereas LXR is expressed constitutively at a very low level. LXR activation by two different LXR agonists strongly interfered with lipopolysaccharide (LPS)- but not with CD40L-induced DC maturation by altering DC morphology, suppressing interleukin-12, but enhancing interleukin-10 secretion. LXR activation in DC largely blocked their T-cell stimulatory ability despite essentially unaltered expression of various antigen-presenting and costimulatory molecules. Immunological 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 DC restored immunological 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 DC in immunity, LXR could be a potential novel target for immunomodulation.
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