F
IPR005384

Duffy antigen/chemokine receptor

InterPro entry
Short nameDuffy_chemokine_rcpt

Description

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
[4]
. 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
[2]
, and endothelial cells, where they may act as either angiogenic or angiostatic factors
[3]
.

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
[17]
. 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
[24, 25]
. 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
[21, 23]
, 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
[22, 9, 11, 10, 6]
, it has also been shown to internalise chemokines but not scavenge them
[8]
. Although DARC is a 7-transmembrane protein, sharing a high content of α-helical secondary structure typical of chemokine structures
[15]
, 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
[16, 5, 19, 18, 20]
. 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
[1]
. There is evidence suggesting a role for DARC in neutrophil migration from the blood into the tissues
[13]
and in modulating inflammatory response
[12, 16, 14, 7, 5]
.

References

1.International union of pharmacology. XXII. Nomenclature for chemokine receptors. Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA. Pharmacol. Rev. 52, 145-76, (2000). PMID: 10699158

2.Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA. Proc. Natl. Acad. Sci. U.S.A. 95, 9448-53, (1998). View articlePMID: 9689100

3.The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, Dzuiba J, Van Damme J, Walz A, Marriott D. J. Biol. Chem. 270, 27348-57, (1995). View articlePMID: 7592998

4.Chemokine receptors. Horuk R. Cytokine Growth Factor Rev. 12, 313-35, (2001). View articlePMID: 11544102

5.The Duffy antigen/receptor for chemokines (DARC) is expressed in endothelial cells of Duffy negative individuals who lack the erythrocyte receptor. Peiper SC, Wang ZX, Neote K, Martin AW, Showell HJ, Conklyn MJ, Ogborne K, Hadley TJ, Lu ZH, Hesselgesser J, Horuk R. J. Exp. Med. 181, 1311-7, (1995). View articlePMID: 7699323

6.Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum. McMorran BJ, Wieczorski L, Drysdale KE, Chan JA, Huang HM, Smith C, Mitiku C, Beeson JG, Burgio G, Foote SJ. Science 338, 1348-51, (2012). View articlePMID: 23224555

7.Expression of DARC, CXCR3 and CCR5 in giant cell arteritis. Bruhl H, Vielhauer V, Weiss M, Mack M, Schlondorff D, Segerer S. Rheumatology (Oxford) 44, 309-13, (2005). View articlePMID: 15572394

8.The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Pruenster M, Mudde L, Bombosi P, Dimitrova S, Zsak M, Middleton J, Richmond A, Graham GJ, Segerer S, Nibbs RJ, Rot A. Nat. Immunol. 10, 101-8, (2009). View articlePMID: 19060902

9.Expression of the Duffy antigen in K562 cells. Evidence that it is the human erythrocyte chemokine receptor. Chaudhuri A, Zbrzezna V, Polyakova J, Pogo AO, Hesselgesser J, Horuk R. J. Biol. Chem. 269, 7835-8, (1994). PMID: 8132497

10.From malaria to chemokine receptor: the emerging physiologic role of the Duffy blood group antigen. Hadley TJ, Peiper SC. Blood 89, 3077-91, (1997). View articlePMID: 9129009

11.Identification and characterization of a promiscuous chemokine-binding protein in a human erythroleukemic cell line. Horuk R, Wang ZX, Peiper SC, Hesselgesser J. J. Biol. Chem. 269, 17730-3, (1994). PMID: 7517400

12.Exaggerated response to endotoxin in mice lacking the Duffy antigen/receptor for chemokines (DARC). Dawson TC, Lentsch AB, Wang Z, Cowhig JE, Rot A, Maeda N, Peiper SC. Blood 96, 1681-4, (2000). PMID: 10961863

13.Duffy antigen facilitates movement of chemokine across the endothelium in vitro and promotes neutrophil transmigration in vitro and in vivo. Lee JS, Frevert CW, Wurfel MM, Peiper SC, Wong VA, Ballman KK, Ruzinski JT, Rhim JS, Martin TR, Goodman RB. J. Immunol. 170, 5244-51, (2003). PMID: 12734373

14.Contribution of Duffy antigen to chemokine function. Rot A. Cytokine Growth Factor Rev. 16, 687-94, (2005). View articlePMID: 16054417

15.One-step immunopurification and lectinochemical characterization of the Duffy atypical chemokine receptor from human erythrocytes. Grodecka M, Bertrand O, Karolak E, Lisowski M, Wasniowska K. Glycoconj. J. 29, 93-105, (2012). View articlePMID: 22246380

16.Expression of the duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium. Patterson AM, Siddall H, Chamberlain G, Gardner L, Middleton J. J. Pathol. 197, 108-16, (2002). View articlePMID: 12081195

17.Chemokines: a new classification system and their role in immunity. Zlotnik A, Yoshie O. Immunity 12, 121-7, (2000). View articlePMID: 10714678

18.Postcapillary venule endothelial cells in kidney express a multispecific chemokine receptor that is structurally and functionally identical to the erythroid isoform, which is the Duffy blood group antigen. Hadley TJ, Lu ZH, Wasniowska K, Martin AW, Peiper SC, Hesselgesser J, Horuk R. J. Clin. Invest. 94, 985-91, (1994). View articlePMID: 8083383

19.Expression of chemokine receptors by subsets of neurons in the central nervous system. Horuk R, Martin AW, Wang Z, Schweitzer L, Gerassimides A, Guo H, Lu Z, Hesselgesser J, Perez HD, Kim J, Parker J, Hadley TJ, Peiper SC. J. Immunol. 158, 2882-90, (1997). PMID: 9058825

20.Up-regulation of Duffy antigen receptor expression in children with renal disease. Liu XH, Hadley TJ, Xu L, Peiper SC, Ray PE. Kidney Int. 55, 1491-500, (1999). View articlePMID: 10201015

21.Cloning of glycoprotein D cDNA, which encodes the major subunit of the Duffy blood group system and the receptor for the Plasmodium vivax malaria parasite. Chaudhuri A, Polyakova J, Zbrzezna V, Williams K, Gulati S, Pogo AO. Proc. Natl. Acad. Sci. U.S.A. 90, 10793-7, (1993). View articlePMID: 8248172

22.A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor. Horuk R, Chitnis CE, Darbonne WC, Colby TJ, Rybicki A, Hadley TJ, Miller LH. Science 261, 1182-4, (1993). View articlePMID: 7689250

23.Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Tournamille C, Colin Y, Cartron JP, Le Van Kim C. Nat. Genet. 10, 224-8, (1995). View articlePMID: 7663520

24.Macrophage inflammatory protein 3alpha is involved in the constitutive trafficking of epidermal langerhans cells. Charbonnier AS, Kohrgruber N, Kriehuber E, Stingl G, Rot A, Maurer D. J. Exp. Med. 190, 1755-68, (1999). View articlePMID: 10601351

25.Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. J. Exp. Med. 187, 875-83, (1998). View articlePMID: 9500790

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