The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity.
The Duffy antigen receptor for chemokines (DARC) belongs to a family of 'silent' heptahelical chemokine receptors that do not couple to G proteins and fail to transmit measurable intracellular signals. DARC binds most inflammatory chemokines and is prominently expressed on venular endothelial cells, where its function has remained contentious. Here we show that DARC, like other silent receptors, internalized chemokines but did not effectively scavenge them. Instead, DARC mediated chemokine transcytosis, which led to apical retention of intact chemokines and more leukocyte migration across monolayers expressing DARC. Mice overexpressing DARC on blood vessel endothelium had enhanced chemokine-induced leukocyte extravasation and contact-hypersensitivity reactions. Thus, interactions of chemokines with DARC support their activity on apposing leukocytes in vitro and in vivo.
Pruenster
Monika
M
Experimental Pathology, Novartis Institutes for BioMedical Research, Vienna A-1230, Austria.
Mudde
Liesbeth
L
Bombosi
Paula
P
Dimitrova
Svetla
S
Zsak
Marion
M
Middleton
Jim
J
Richmond
Ann
A
Graham
Gerard J
GJ
Segerer
Stephan
S
Nibbs
Robert J B
RJ
Rot
Antal
A
D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D004285:Dogs; D004375:Duffy Blood-Group System / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000276:immunology*; D051379:Mice; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
C473745:ACKR1 protein, human; D018925:Chemokines; D004375:Duffy Blood-Group System; D011956:Receptors, Cell Surface