Topical application of sphingosine-1-phosphate and FTY720 attenuate allergic contact dermatitis reaction through inhibition of dendritic cell migration.
Migration of Langerhans cells (LCs) from the skin to the lymph node is an essential step in the pathogenesis of allergic contact dermatitis (ACD). Therefore, inhibition of LC-migration could be a promising strategy to improve this skin disease. Effects of sphingosine-1-phosphate (S1P) and the immunomodulator FTY720 on LC trafficking is not well defined, yet. Thus, we investigated the action of topically administered S1P and FTY720 in a murine model of ACD. Most interestingly, FTY720 as well as S1P inhibited the inflammatory reaction in the elicitation phase of ACD. In the sensitization phase, FTY720, and S1P reduced the weight and cell count of the draining auricular lymph node, as well as immigrated dendritic cells provoked by repetitive topical administration of the hapten. Correspondingly, the density of LCs in the epidermis was higher in FTY720- and S1P-treated mice compared to vehicle treatment. A skin dendritic cell migration assay confirmed the significant inhibition of dendritic cell migration by FTY720 and S1P. These data supply conclusive evidence that the strategy of targeting the migratory response of LCs with locally acting S1P or FTY720 represents an emerging option in the treatment of allergic skin diseases like contact hypersensitivity and atopic dermatitis.
Reines
Ilka
I
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.
Kietzmann
Manfred
M
Mischke
Reinhard
R
Tschernig
Thomas
T
Lüth
Anja
A
Kleuser
Burkhard
B
Bäumer
Wolfgang
W
D000287:Administration, Topical; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D017449:Dermatitis, Allergic Contact / Q000517:prevention & control*; D005260:Female; D000068876:Fingolimod Hydrochloride; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008246:Lysophospholipids / Q000008:administration & dosage* / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D010069:Oxadiazoles / Q000008:administration & dosage; D011409:Propylene Glycols / Q000008:administration & dosage*; D049349:Receptors, Lysosphingolipid / Q000502:physiology; D012867:Skin / Q000166:cytology; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D013876:Thiophenes / Q000008:administration & dosage; D014051:Toluene 2,4-Diisocyanate
D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D010069:Oxadiazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; D014051:Toluene 2,4-Diisocyanate; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine