Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Originally published online as doi:10.1189/jlb.0108047 on May 30, 2008

Published online before print May 30, 2008
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(Journal of Leukocyte Biology. 2008;84:871-879.)
© 2008 by Society for Leukocyte Biology

Selected natural and synthetic retinoids impair CCR7- and CXCR4-dependent cell migration in vitro and in vivo

Eduardo J. Villablanca*,{dagger}, Dan Zhou{ddagger}, Barbara Valentinis{ddagger}, Aurora Negro*, Laura Raccosta*, Laura Mauri§, Alessandro Prinetti§, Sandro Sonnino§, Claudio Bordignon*,{dagger},{ddagger}, Catia Traversari{ddagger} and Vincenzo Russo*,1

* Cancer Gene Therapy Unit, Cancer Immunotherapy and Gene Therapy Program, Scientific Institute H. San Raffaele, Milan, Italy;
{dagger} Università Vita-Salute San Raffaele, Milan, Italy;
{ddagger} MolMed S.p.A., Milan, Italy;
§ Department of Medical Chemistry, Biochemistry and Biotechnology, Center of Excellence on Neurodegenerative Diseases, University of Milan, LITA, Segrate, Italy

1 Correspondence: Cancer Gene Therapy Unit, Cancer Immunotherapy and Gene Therapy Program, Dept. of Oncology, Scientific Institute S. Raffaele, Via Olgettina 58, Milan, Italy. E-mail: v.russo{at}hsr.it

ABSTRACT

Dendritic cell (DC) migration to secondary lymphoid organs is a crucial step to initiate adaptive immune responses. This step requires the expression of a functional CCR7 chemokine receptor on DC undergoing maturation. Here, we show that the natural retinoid 9-cis retinoic acid (9cRA) and the synthetic retinoid fenretinide (4-HPR) specifically inhibit the functional up-regulation of CCR7 on maturing human DCs, without affecting early steps of DC maturation. As a consequence, mature DCs do not migrate in vitro toward the chemokine CCL19. Importantly, 4-HPR and 9cRA by inhibiting the expression of CCR7 on bone marrow-derived murine DCs dampen their in vivo migration to draining lymph nodes. 4-HPR also inhibits the expression of the chemokine receptors CXCR4, therefore, impairing in vitro migration of human DCs to CXCL12 and inhibiting in vivo the CXCR4-dependent migration of the posterior lateral line primordium (PLLp) in zebrafish embryos. Taken together, these data highlight a novel function of retinoids and suggest the possibility of using retinoids to treat inflammatory or autoimmune diseases.

Key Words: dendritic cells • chemokine receptors • zebrafish






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