Abstract
Leukocyte functions are linked to their migratory responses, which, in turn, are largely determined by the expression profile of classical chemokine receptors. Upon binding their cognate chemokines, these G-protein-coupled receptors (GPCRs) initiate signaling cascades and downstream molecular and cellular responses, including integrin activation and cell locomotion. Chemokines also bind to an alternative subset of chemokine receptors, which have serpentine structure characteristic for GPCRs but lack DRYLAIV consensus motive required for coupling to G-proteins. Duffy antigen receptor for chemokines (DARC) is a member of this atypical receptor subfamily. DARC binds a broad range of inflammatory CXC and CC chemokines and is expressed by erythrocytes, venular endothelial cells, and cerebellar neurons. Erythrocyte DARC serves as blood reservoir of cognate chemokines but also as a chemokine sink, buffering potential surges in plasma chemokine levels. Endothelial cell DARC internalizes chemokines on the basolateral cell surface resulting in subsequent transcytosis of chemokines and their immobilization on the tips of apical microvilli. These DARC-mediated endothelial cell interactions allow chemokines produced in the extravascular tissues to optimally function as arrest chemokines on the luminal endothelial cell surface.
Highlights
Chemokines bind to an alternative subset of chemokine receptors, which have serpentine structure characteristic for G-protein-coupled receptors (GPCRs) but lack DRYLAIV consensus motive required for coupling to G-proteins
Further investigation into the role of Duffy antigen receptor for chemokines (DARC) in acute lung inflammation revealed that a lack of DARC in mice results in down-regulation of CXCR2 on neutrophils because of high levels of circulating chemokines during severe inflammation (Zarbock et al, 2010). It this study DARC was essential for chemokinemediated leukocyte recruitment, whereby DARC KO animals were protected from acid-induced lung injury and experienced preserved oxygenation
Since the discovery of its chemokine-binding properties, DARC has been mainly considered as a“decoy” receptor scavenging its ligands
Summary
Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Novitzky-basso, I & Rot, A 2012, 'Duffy antigen receptor for chemokines and its involvement in patterning and control of inflammatory chemokines', Frontiers in immunology, vol 3, 266. https://doi.org/10.3389/fimmu.2012.00266
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