CDB15:0000408 CXCL1 — ACKR1
Experimentally validated in Human, Mixed species; Orthology-inferred in Human, Rat, Chicken, Macaque, Pig, Cow, Chimp, Horse, Marmoset
Title
Journal:; Year Published:
Abstract
Duffy antigen facilitates movement of chemokine across the endothelium in vitro and promotes neutrophil transmigration in vitro and in vivo.
Journal of immunology, 2003; PubMed, Homo sapiens CXCL1 — Homo sapiens ACKR1
ABSTRACT: The Duffy Ag expressed on RBCs, capillaries, and postcapillary venular endothelial cells binds selective CXC and CC chemokines with high affinity. Cells transfected with the Duffy Ag internalize but do not degrade chemokine ligand. It has been proposed that Duffy Ag transports chemokines across the endothelium. We hypothesized that Duffy Ag participates in the movement of chemokines across the endothelium and, by doing so, modifies neutrophil transmigration. We found that the Duffy Ag transfected into human endothelial cells facilitates movement of the radiolabeled CXC chemokine, growth related oncogene-alpha/CXC chemokine ligand 1 (GRO-alpha/CXCL1), across an endothelial monolayer. In addition, neutrophil migration toward GRO-alpha/CXCL1 and IL-8 (IL-8/CXCL8) was enhanced across an endothelial monolayer expressing the Duffy Ag. Furthermore, GRO-alpha/CXCL1 stimulation of endothelial cells expressing the Duffy Ag did not affect gene expression by oligonucleotide microarray analysis. These in vitro observations are supported by the finding that IL-8/CXCL8-driven neutrophil recruitment into the lungs was markedly attenuated in transgenic mice lacking the Duffy Ag. We conclude that Duffy Ag has a role in enhancing leukocyte recruitment to sites of inflammation by facilitating movement of chemokines across the endothelium.
A high endothelial venule-expressing promiscuous chemokine receptor DARC can bind inflammatory, but not lymphoid, chemokines and is dispensable for lymphocyte homing under physiological conditions.
International immunology, 2003; PubMed, Homo sapiens CXCL1 — Mus Musculus Ackr1
ABSTRACT: Chemokines displayed on the luminal surface of blood vessels play pivotal roles in inflammatory and homeostatic leukocyte trafficking in vivo. However, the mechanisms underlying the functional regulation of chemokines on the endothelial cell surface remain ill-defined. A promiscuous chemokine receptor, the Duffy antigen receptor for chemokines (DARC), has been implicated in the regulation of chemokine functions. Here we show that DARC is selectively expressed at the mRNA and protein levels in the high endothelial venules (HEV) of unstimulated lymph nodes (LN). To examine the biological significance of DARC expression in HEV, we performed competitive binding experiments with 20 different chemokines. The results showed that DARC selectively bound distinct members of the pro-inflammatory chemokines such as CXCL1, CXCL5, CCL2, CCL5 and CCL7, but not lymphoid chemokines such as CCL21, CCL19, CXCL12 and CXCL13 that are normally expressed in HEV. CCL2 bound to DARC failed to induce a significant cytosolic [Ca(2+)] elevation in CCR2B-expressing cells, whereas the free form of CCL2 induced a distinct [Ca(2+)] elevation, suggesting that DARC down-regulates activities of pro-inflammatory chemokines upon binding. Targeted disruption of the gene encoding DARC did not induce any obvious changes in the cell number or leukocyte subsets in the peripheral and mesenteric LN. Neither did DARC deficiency significantly affect lymphocyte migration into LN. These results suggest that DARC may be a scavenger for pro-inflammatory chemokines, but not a presenting molecule for lymphoid chemokines at HEV and that it is probably functionally dispensable for lymphocyte trafficking to HEV-bearing lymphoid tissues under physiological conditions.
The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain.
The Journal of biological chemistry, 1995; PubMed, Homo sapiens CXCL1 — Homo sapiens ACKR1
ABSTRACT: The Duffy antigen (DARC) is a promiscuous chemokine receptor that also binds Plasmodium vivax. DARC belongs to a family of heptahelical chemokine receptors that includes specific (IL-8RA) and shared (IL-8RB) IL-8 receptors. Ligand binding specificity of IL-8 receptors was localized to the amino-terminal extracellular (E1) domain. To determine the basis for promiscuous chemokine binding by DARC, a chimeric receptor composed of the E1 domain of DARC and hydrophobic helices and loops from IL-8RB (DARCe1/IL-8RB) was constructed. Scatchard analysis of stable transfectants demonstrated that the DARCe1/IL-8RB chimeric receptor bound IL-8 and melanoma growth stimulating activity (MGSA) with KD values almost identical to the native receptors. The hybrid receptor also bound RANTES, MCP-1, and MGSA-E6A (which binds DARC, but not IL-8RB), but not MIP-1 alpha, similarly to DARC. Ligand binding to DARC transfectants was unaltered by anti-Fy3, but inhibited by Fy6, which binds an epitope in the E1 domain. The epitope recognized by Fy3 was localized to the third extracellular loop by analysis of insect cells expressing chimeric receptors composed of complementary portions of DARC and IL-8RB. These findings implicate the E1 domain of DARC in multispecific chemokine binding.