CXCL12-CXCR4 engagement is required for migration of cutaneous dendritic cells.
CCR7 is regarded as an essential chemokine receptor for cutaneous dendritic cell (DC) migration into the regional lymph nodes. However, complete migratory inhibition cannot be obtained in CCR7-deficient mice, suggesting that there exist other chemokine receptors involved in this process. Initially, we found that CXCR4 was highly expressed on migrated cutaneous DCs and that its ligand, CXCL12, was detected in the LYVE-1(+) lymphatic vessels in the skin. FITC-induced cutaneous DC migration into the draining lymph nodes was impaired by the specific CXCR4 antagonist 4-F-Benzoyl-TN14003. Among FITC(+) cells, Langerin(+) Langerhans cells and Langerin(-) (dermal) dDC subsets were detected as CD11c(high+)CD11b(int+) cells and CD11c(high+)CD11b(high+) plus CD11c(low+)CD11b(int+) cells, respectively, both of which were suppressed by CXCR4 antagonist. Moreover, in vivo contact hypersensitivity response was impaired by CXCR4 antagonist administered during the sensitization phase. The in vitro proliferative response to dinitrobenzene sulfonic acid of sensitized lymph node cells was inhibited by CXCR4 antagonist treatment. These findings demonstrated that CXCL12-CXCR4 engagement on cutaneous DCs plays a crucial role in the initiation of skin immune response by enhancing cutaneous DC migration.
Kabashima
Kenji
K
Department of Dermatology, University of Environmental and Occupational Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. kkabashi@med.uoeh-u.ac.jp
Shiraishi
Noriko
N
Sugita
Kazunari
K
Mori
Tomoko
T
Onoue
Ayako
A
Kobayashi
Miwa
M
Sakabe
Jun-Ichi
J
Yoshiki
Ryutaro
R
Tamamura
Hirokazu
H
Fujii
Nobutaka
N
Inaba
Kayo
K
Tokura
Yoshiki
Y
D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D039521:CD11c Antigen / Q000032:analysis; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004817:Epidermis / Q000276:immunology; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D007801:Langerhans Cells / Q000187:drug effects / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D042601:Lymphatic Vessels; D051379:Mice; D008810:Mice, Inbred C57BL; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000276:immunology*