CDB15:0000240 CCL2 — ACKR1
Experimentally validated in Human, Mixed species, Mouse; Orthology-inferred in Human, Mouse, Rat, Chicken, Macaque, Pig, Dog, Cow, Chimp, Horse, Marmoset, Sheep
Title
Journal:; Year Published:
Abstract
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 CCL2 — 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 human Duffy antigen binds selected inflammatory but not homeostatic chemokines.
Biochemical and biophysical research communications, 2004; PubMed, Homo sapiens CCL2 — Homo sapiens ACKR1
ABSTRACT: The aim of the study was to compare the ability of the human Duffy antigen to bind homeostatic and inflammatory chemokines. Homeostatic chemokines did not bind to the Duffy antigen on erythrocytes with high affinity. In contrast, 60% of inflammatory chemokines bound strongly to Duffy, with no obvious preference for CXC or CC classes. It was investigated if this binding profile was reflected in the binding pattern of endothelial cells. Two examples of homeostatic (125I-CXCL12 and 125I-CCL21) and inflammatory (125I-CXCL8 and 125I-CCL5) chemokines were incubated with human synovia. In agreement with the erythrocyte binding data, intense specific signals for CXCL8 and CCL5 binding were found on endothelial cells, whereas CXCL12 and CCL21 showed only weak binding to these cells. Our study provides evidence that the human Duffy antigen binds selected inflammatory, but not homeostatic, chemokines and that this binding pattern is reflected by endothelial cells within inflamed and non-inflamed tissue.
Identification of mouse Duffy antigen receptor for chemokines (Darc) as a BMD QTL gene.
Genome research, 2007; PubMed, Mus Musculus Ccl2 — Mus Musculus Ackr1
ABSTRACT: It is now well known that bone mineral density (BMD) variance is determined by both genetic and environmental factors. Accordingly, studies in human and animal models have revealed evidence for the presence of several quantitative trait loci (QTL) that contribute to BMD variations. However, the identification of BMD QTL genes remains a big challenge. In the current study, we focused our efforts to identify the BMD candidate gene in chromosome 1 (Chr 1) QTL that was detected from a cross involving high BMD CAST/EiJ (CAST) and low BMD C57BL/6J (B6) mice. To this end, we have combined several approaches including: (1) fine mapping the BMD QTL in Chr 1 of the B6.CAST F2 female mice using a large number of polymorphic markers; (2) the generation of congenic sublines of mice by repeated backcrossing of CAST with B6 mice and phenotype characterization; (3) expression profiling genes in the QTL region; and (4) SNP analyses to identify the mouse Duffy Antigen Receptor for Chemokines (Darc) as a candidate gene for Chr 1 BMD QTL2. We verified the involvement of the Darc protein in BMD variation by evaluating the skeletal phenotype of Darc-knockout mice and congenic sublines of mice carrying small chromosomal segments from CAST BMD QTL. Based on the findings that Darc-antibody blocked formation of multinucleated osteoclasts in vitro and that Darc from CAST binds chemokines, known to regulate osteoclast formation, with reduced affinity compared with Darc from B6 mice, we conclude that Darc regulates BMD negatively by increasing osteoclast formation, and that the genetic association between Darc gene polymorphism and BMD variations in humans merits investigation.