Maturing dendritic cells depend on RAGE for in vivo homing to lymph nodes.
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.
Manfredi
Angelo A
AA
Clinical Immunology Unit, H. San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Via Olgettina 48, Milan, Italy. manfredi.angelo@hsr.it
Capobianco
Annalisa
A
Esposito
Antonio
A
De Cobelli
Francesco
F
Canu
Tamara
T
Monno
Antonella
A
Raucci
Angela
A
Sanvito
Francesca
F
Doglioni
Claudio
C
Nawroth
Peter P
PP
Bierhaus
Angelika
A
Bianchi
Marco E
ME
Rovere-Querini
Patrizia
P
Del Maschio
Alessandro
A
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D019204:GTP-Binding Proteins; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019204:GTP-Binding Proteins