The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity

Pruenster, Monika; Mudde, Liesbeth; Bombosi, Paula; Dimitrova, Svetla; Zsak, Marion; Middleton, Jim; Richmond, Ann; Graham, Gerard J.; Segerer, Stephan; Nibbs, Robert J. B.; Rot, Antal

doi:10.1038/ni.1675

Cited by 280 publications

(317 citation statements)

References 52 publications

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“…In general, CXC chemokines bind CXC receptors and CC chemokines bind CC receptors, but a subset of CXC chemokines that are agonists for the CXCR3 receptor also bind the CCR3 receptor not as an agonist but as an antagonist (40). Further, the human chemokine receptor DARC can bind both CXC and CC chemokines with high affinity, but DARC is not a signaling receptor and is believed to play a role in trafficking chemokines (41). Currently, nothing is known regarding what, if any, role(s) the CXC/CC motif plays in CXC/CC chemokine structure and receptor function.…”

Section: Discussionmentioning

confidence: 99%

Probing the Role of CXC Motif in Chemokine CXCL8 for High Affinity Binding and Activation of CXCR1 and CXCR2 Receptors*

Joseph¹,

Sarmiento²,

Mishra³

et al. 2010

Journal of Biological Chemistry

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All chemokines share a common structural scaffold that mediate a remarkable variety of functions from immune surveillance to organogenesis. Chemokines are classified as CXC or CC on the basis of conserved cysteines, and the two subclasses bind distinct sets of GPCR class of receptors and also have markedly different quaternary structures, suggesting that the CXC/CC motif plays a prominent role in both structure and function. For both classes, receptor activation involves interactions between chemokine N-loop and receptor N-domain residues (Site-I), and between chemokine N-terminal and receptor extracellular/ transmembrane residues (Site-II). We engineered a CC variant (labeled as CC-CXCL8) of the chemokine CXCL8 by deleting residue X (CXC 3 CC), and found its structure is essentially similar to WT. In stark contrast, CC-CXCL8 bound poorly to its cognate receptors CXCR1 and CXCR2 (K i > 1 M). Further, CC-CXCL8 failed to mobilize Ca 2؉ in CXCR2-expressing HL-60 cells or recruit neutrophils in a mouse lung model. However, most interestingly, CC-CXCL8 mobilizes Ca 2؉ in neutrophils and in CXCR1-expressing HL-60 cells. Compared with the WT, CC-CXCL8 binds CXCR1 N-domain with only ϳ5-fold lower affinity indicating that the weak binding to intact CXCR1 must be due to its weak binding at Site-II. Nevertheless, this level of binding is sufficient for receptor activation indicating that affinity and activity are separable functions. We propose that the CXC motif functions as a conformational switch that couples Site-I and Site-II interactions for both receptors, and that this coupling is critical for high affinity binding but differentially regulates activation.Chemokines mediate a wide variety of biological functions from recruiting leukocytes to the site of injury and infection to organ development, wound healing, and angiogenesis (1-4). Chemokines are characterized by four conserved cysteines that form disulfide bonds, and are classified into CXC and CC families based on cysteine pattern near the N terminus. CXC ligands bind and activate only CXC receptors and CC ligands bind and activate only CC receptors, indicating functional divergence could be as old as the molecules themselves. Structure-function studies consistently show that binding and receptor activation for both classes involves two interactions: between the ligand N-loop and receptor N-domain residues (Site-I) and between the ligand N-terminal and receptor extracellular/transmembrane residues (Site-II) (5-9).Structures of several CXC and CC chemokines have been solved by NMR and x-ray crystallography, and reveal a common structural fold (known as chemokine fold) at the monomer level (10 -15). The CXC/CC motif connects the functionally important N-loop and N-terminal residues, and also plays a structural role by forming disulfide bonds that tether the N-terminal and N-loop residues to the protein core (Fig. 1). In the CXC chemokine CXCL8 (also known as interleukin-8, IL-8), the residue corresponding to X (Gln) in the CXC motif has been mutated with no effec...

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Section: Discussionmentioning

confidence: 99%

Probing the Role of CXC Motif in Chemokine CXCL8 for High Affinity Binding and Activation of CXCR1 and CXCR2 Receptors*

Joseph¹,

Sarmiento²,

Mishra³

et al. 2010

Journal of Biological Chemistry

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“…37 Supporting this, studies in mouse models show that DARC expression on both RBC and endothelial cells influences neutrophil migration. 38,39 In addition, DARC Ϫ46C/C may associate with impaired hematopoiesis because some of the chemokines that bind to DARC (eg, GRO␣ 40 ) regulate many hematopoietic responses, including survival, proliferation, migration, and homing. 41 Supporting this possibility, healthy subjects of African ancestry have reduced numbers of bone marrow progenitor cells than Caucasians.…”

Section: Discussionmentioning

confidence: 99%

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry

Kulkarni

Marconi

et al. 2009

Blood

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Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects, we show that, although leukopenia (< 4000 WBC/mm 3 during infection) was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The Africanspecific ؊46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AAs). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4 ؉ T-cell counts, such that leukopenic but not nonleukopenic HIV ؉ AAs with DARC ؊46C/C had a survival advantage compared with all Duffypositive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIVinfected AAs, despite immunodeficiency.

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“…The expression of KC (the mouse ortholog of human CXCL1) and DARC was found to follow parallel temporal patterns and tissue localization during mouse development (28), suggesting that a relationship may exist between the two. In general, DARC was found to maintain chemokine homeostasis in the blood (29) and to facilitate chemokine transcytosis and presentation across endothelium (30,31).…”

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confidence: 99%

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

Al-Alwan

Chang

Rousseau

et al. 2014

The Journal of Immunology

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Airway smooth muscle cell (ASMC) migration is an important mechanism postulated to play a role in airway remodeling in asthma. CXCL1 chemokine has been linked to tissue growth and metastasis. In this study, we present a detailed examination of the inhibitory effect of CXCL1 on human primary ASMC migration and the role of the decoy receptor, Duffy AgR for chemokines (DARC), in this inhibition. Western blots and pathway inhibitors showed that this phenomenon was mediated by activation of the ERK-1/2 MAPK pathway, but not p38 MAPK or PI3K, suggesting a biased selection in the signaling mechanism. Despite being known as a nonsignaling receptor, small interference RNA knockdown of DARC showed that ERK-1/2 MAPK activation was significantly dependent on DARC functionality, which, in turn, was dependent on the presence of heat shock protein 90 subunit α. Interestingly, DARC- or heat shock protein 90 subunit α–deficient ASMCs responded to CXCL1 stimulation by enhancing p38 MAPK activation and ASMC migration through the CXCR2 receptor. In conclusion, we demonstrated DARC’s ability to facilitate CXCL1 inhibition of ASMC migration through modulation of the ERK-1/2 MAPK–signaling pathway.

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The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity

Cited by 280 publications

References 52 publications

Probing the Role of CXC Motif in Chemokine CXCL8 for High Affinity Binding and Activation of CXCR1 and CXCR2 Receptors*

Probing the Role of CXC Motif in Chemokine CXCL8 for High Affinity Binding and Activation of CXCR1 and CXCR2 Receptors*

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

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