A role for multidrug resistance protein 4 (MRP4; ABCC4) in human dendritic cell migration.
The capacity of dendritic cells (DCs) to migrate from peripheral organs to lymph nodes (LNs) is important in the initiation of a T cell-mediated immune response. The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp; ABCB1) and the multidrug resistance protein 1 (MRP1; ABCC1) have been shown to play a role in both human and murine DC migration. Here we show that a more recently discovered family member, MRP4 (ABCC4), is expressed on both epidermal and dermal human skin DCs and contributes to the migratory capacity of DCs. Pharmacological inhibition of MRP4 activity or down-regulation through RNAi in DCs resulted in reduced migration of DCs from human skin explants and of in vitro generated Langerhans cells. The responsible MRP4 substrate remains to be identified as exogenous addition of MRP4's known substrates prostaglandin E(2), leukotriene B(4) and D(4), or cyclic nucleotides (all previously implicated in DC migration) could not restore migration. This notwithstanding, our data show that MRP4 is an important protein, significantly contributing to human DC migration toward the draining lymph nodes, and therefore relevant for the initiation of an immune response and a possible target for immunotherapy.
van de Ven
Rieneke
R
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Scheffer
George L
GL
Reurs
Anneke W
AW
Lindenberg
Jelle J
JJ
Oerlemans
Ruud
R
Jansen
Gerrit
G
Gillet
Jean-Pierre
JP
Glasgow
Joel N
JN
Pereboev
Alexander
A
Curiel
David T
DT
Scheper
Rik J
RJ
de Gruijl
Tanja D
TD
D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology*; D000078404:Epidermal Cells; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology; D008198:Lymph Nodes; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D012867:Skin / Q000166:cytology
D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human