Duffy antigen/chemokine receptor (Duffy_chemokine_rcpt)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

This entry represents the Duffy antigen/chemokine receptor, DARC (Duffy Antigen for Chemokines). It is also known as Fy protein , and was originally identified as a blood group antigen. DARC has been found to act as a multi-specific receptor for chemokines of both the C-C and C-X-C families including CCL2, CCL5, CXCL1 and CXCL4 , it has also been shown to internalise chemokines but not scavenge them . Although DARC is a 7-transmembrane protein, sharing a high content of α-helical secondary structure typical of chemokine structures , the characteristic rhodopsin-like signature is virtually absent. As a result, unlike classical chemokine receptors DARC does not signal through G-proteins, so is regarded as an atypical chemokine receptor.

DARC was initially described on red blood cells, but subsequent studies have demonstrated DARC protein expression on renal endothelial and epithelial cells and in Purkinje cells of the cerebellum, even in Duffy-negative individuals whose red cells lack DARC . DARC is believed to play an important role in endothelial cells, since expression on these cell types is highly conserved, whereas the function on RBCs appears to be dispensable in order to confer resistance to malaria . There is evidence suggesting a role for DARC in neutrophil migration from the blood into the tissues and in modulating inflammatory response .