Editors' ChoiceImmunology

Turning to the DARC Side

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Science Signaling  23 Dec 2008:
Vol. 1, Issue 51, pp. ec438
DOI: 10.1126/scisignal.151ec438

Chemokines bind to G protein–coupled receptors (GPCRs) on leukocytes, triggering intracellular pathways to recruit the leukocytes from the circulatory system to sites of inflammation. Although a seven-transmembrane receptor like GPCRs, the Duffy antigen receptor for chemokines (DARC), found in venular endothelial cells, does not couple to G proteins and has been postulated to act, like other nonsignaling receptors in the same family, as a “decoy receptor” that binds to chemokines and internalizes them for lysosomal degradation. Pruenster et al. used immunoelectron microscopy to show that, when DARC-binding chemokine was injected into ex vivo human skin, chemokine and receptor colocalized at the luminal and abluminal surfaces of venular endothelial cells, as well as in intracellular vesicles. Addition of cognate chemokine to the basolateral surface of Madin-Darby canine kidney (MDCK) cell monolayers transfected with DARC elicited the redistribution of DARC and associated chemokine to the apical surface by way of intracellular vesicles. Experiments with MDCK or human umbilical vein endothelial cell (HUVEC) monolayers separating fluid compartments showed that DARC increased transcytosis of undegraded 125I-labeled chemokine in the basolateral to apical direction, with retention of a substantial portion at the apical cell surface. Moreover, DARC promoted apical to basal transmigration of human monocytes across MDCK and HUVEC monolayers in response to chemokine in the basal compartment. Neutrophil recruitment after chemokine injection was enhanced in mice overexpressing DARC in endothelial cells (mDARCtg mice), as were contact hypersensitivity (CHS) and leukocyte migration into CHS skin lesions. Thus, the authors conclude that, rather than acting as a decoy receptor, DARC promotes chemokine-mediated leukocyte migration.

M. Pruenster, L. Mudde, P. Bombosi, S. Dimitrova, M. Zsak, J. Middleton, A. Richmond, G. J. Graham, S. Segerer, R. J. B. Nibbs, A. Rot, The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nat. Immunol. 10, 101–108 (2009). [PubMed]

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