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Maturing Dendritic Cells Depend on RAGE for In Vivo Homing to Lymph Nodes¹

Angelo A. Manfredi^2,*, Annalisa Capobianco^*, Antonio Esposito, Francesco De Cobelli, Tamara Canu, Antonella Monno^*, Angela Raucci, Francesca Sanvito, Claudio Doglioni, Peter P. Nawroth^¶, Angelika Bierhaus^¶, Marco E. Bianchi, Patrizia Rovere-Querini^* and Alessandro Del Maschio

^* Clinical Immunology Unit, Department of Radiology, Department of Pathology, and Chromatin Dynamics Unit, H. San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy; and ^¶ Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany

The mobilization of dendritic cells (DCs) from peripheral tissues is critical for the establishment of T cell-dependent immune responses or tolerance, because the physical interaction of DCs with naive T cells takes place in the T cell areas of lymph nodes. The autocrine/paracrine release of the high mobility group box 1 (HMGB1) nuclear protein by DCs controls the outcome of the DC–T cell interaction, influencing the priming/Th1 polarization of naive T cells. We herein present evidence that the receptor for advanced glycation end products (RAGE), a multiligand member of the Ig superfamily of cell-surface molecules that acts as a receptor for HMGB1, plays a nonredundant role in DC homing to lymph nodes. We used noninvasive imaging by magnetic resonance and immunohistochemistry to track DCs after s.c. injection in the footpad of wild-type^+/+ or RAGE^–/– mice. Maturing DCs expressing RAGE effectively migrated in both conditions. In contrast, RAGE^–/– DCs failed to reach the draining popliteal lymph nodes of +/+ and –/– mice, indicating that the integrity of RAGE is required for DC mobilization. Thus the HMGB1-RAGE pathway is a checkpoint in DC maturation and function and a candidate for targeted therapies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Associazione Italiana per la Ricerca sul Cancro, the Ministero della Salute, and the Ministero dell’Università e della Ricerca.

² Address correspondence and reprint requests to Dr. Angelo A. Manfredi, H. San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Via Olgettina 48, Milan, 20132 Italy. E-mail address: manfredi.angelo{at}hsr.it

³ Abbreviations used in this paper: DC, dendritic cell; HMGB1, high mobility group box 1 (nuclear protein); MRI, magnetic resonance imaging; RAGE, receptor for advanced glycation end products; SPIO, superparamagnetic iron oxide particles.