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Erythrocyte Duffy antigen receptor for chemokines (DARC): diagnostic and therapeutic implications in atherosclerotic cardiovascular disease.

ABSTRACT: Atherosclerosis is an inflammatory disease. The last three decades efforts have been made to elucidate the biochemical pathways that are implicated in the process of atherogenesis and plaque development. Chemokines are crucial mediators in every step of this process. Additionally, cellular components of the peripheral blood have been proved important mediators in the formation and progression of atherosclerotic lesions. However, until recently data were mostly focusing on leukocytes and platelets. Erythrocytes were considered unreceptive bystanders and limited data supported their importance in the progression and destabilization of the atherosclerotic plaque. Recently erythrocytes, through their Duffy antigen receptor for chemokines (DARC), have been proposed as appealing regulators of chemokine-induced pathways. Dissimilar to every other chemokine receptor DARC possesses high affinity for several ligands from both CC and CXC chemokine sub-families. Moreover, DARC is not coupled to a G-protein or any other intracellular signalling system; thus it is incapable of generating second messages. The exact biochemical role of erythrocyte DARC remains to be determined. It is however challenging the fact that DARC is a regulator of almost every CC and CXC chemokine ligand and therefore DARC antagonism could effectively block the complex pre-inflammatory chemokine network. In the present review we intent to provide recent evidence supporting the role of erythrocytes in atherosclerosis focusing on the erythrocyte-chemokine interaction through the Duffy antigen system.

SUBMITTER: Apostolakis S

PROVIDER: S-EPMC4001982 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Erythrocyte Duffy antigen receptor for chemokines (DARC): diagnostic and therapeutic implications in atherosclerotic cardiovascular disease.

Apostolakis Stavros S Chalikias Georgios K GK Tziakas Dimitrios N DN Konstantinides Stavros S

Acta pharmacologica Sinica 20110328 4

Atherosclerosis is an inflammatory disease. The last three decades efforts have been made to elucidate the biochemical pathways that are implicated in the process of atherogenesis and plaque development. Chemokines are crucial mediators in every step of this process. Additionally, cellular components of the peripheral blood have been proved important mediators in the formation and progression of atherosclerotic lesions. However, until recently data were mostly focusing on leukocytes and platelet ...[more]

PMID: 21441947

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Project description:Neutrophils are well-recognized for their pathogen killing mechanisms and disorders of neutrophil count and function are associated with recurrent infections. The Duffy Antigen Receptor for Chemokines (DARC)-null genotype is predominant in sub-Saharan African ancestry populations and is the major genetic determinant of benign ethnic neutropenia which has been associated with increased risk of Human Immunodeficiency Virus (HIV)-1 acquisition and mother-to-child transmission. However, the impact of DARC-null-linked neutropenia on HIV disease progression remains controversial. While the DARC-null genotype is associated with low numbers of circulating neutrophils, the effects of the polymorphism on neutrophil functions is unknown. We investigated the impact of the DARC-null trait and lower absolute neutrophil counts (ANCs) on key neutrophil effector functions [proteolytic activity within the phagosome following Fc receptor-mediated phagocytosis, reactive oxygen species (ROS) production, and neutrophil extracellular trap (NET) formation] in 20 HIV negative and 22 HIV-1 chronically infected black South Africans. Phagosome maturation was measured by flow cytometry following Fc-mediated uptake of IgG opsonized beads; ROS production was measured by chemi-luminescence after activation of neutrophils with phorbol 12-myristate 13-acetate (PMA). Activated neutrophils were also visualized by fluorescent microscopy for NET quantification. Study subjects were genotyped for the DARC trait using TaqMan allelic discrimination assays and ANCs were measured by full blood count. As expected, the DARC-null polymorphism was highly prevalent in our participant cohort (69%) and was strongly associated with lower ANCs in uninfected (p = 0.0007) and HIV-1 infected (p = 0.03) subjects. We observed enhanced proteolytic activity within the phagosome in the absence of DARC at 10 min (p = 0.05 and p = 0.009) and 60 min (p = 0.05 and p = 0.07) in uninfected and HIV-1 infected subjects, respectively. ROS was unaffected by DARC trait irrespective of HIV status. Furthermore, formation of NETs was reduced in neutrophils from DARC-null subjects (p = 0.04) following prolonged in vitro stimulation, but only in HIV-1 infected subjects. The data indicate differential neutrophil function in the absence of DARC that may be moderately modulated by HIV-1 infection but overall, the data suggest that DARC-null trait is not deleterious to neutrophil effector functions in African populations.

Project description:There is now considerable experimental data to suggest that inflammatory cells collaborate in the healing of skeletal fractures. In terms of mechanisms that contribute to the recruitment of inflammatory cells to the fracture site, chemokines and their receptors have received considerable attention. Our previous findings have shown that Duffy antigen receptor for chemokines (Darc), the non-classical chemokine receptor that does not signal, but rather acts as a scavenger of chemokines that regulate cell migration, is a negative regulator of peak bone density in mice. Furthermore, because Darc is expressed by inflammatory and endothelial cells, we hypothesized that disruption of Darc action will affect post-fracture inflammation and consequently will affect fracture healing. To test this hypothesis, we evaluated fracture healing in mice with targeted disruption of Darc and corresponding wild type (WT) control mice. We found that fracture callus cartilage formation was significantly greater (33%) at 7 days post-surgery in Darc-KO compared to WT mice. The increased cartilage was associated with greater Collagen (Col) II expression at 3 days post-fracture and Col-X at 7 days post-fracture compared to WT mice, suggesting that Darc deficiency led to early fracture cartilage formation and differentiation. We then compared the expression of cytokine and chemokine genes known to be induced during inflammation. Interleukin (Il)-1?, Il-6, and monocyte chemotactic protein 1 were all down regulated in the fractures derived from Darc-KO mice at one day post-fracture, consistent with an altered inflammatory response. Furthermore, the number of macrophages was significantly reduced around the fractures in Darc-KO compared to WT mice. Based on these data, we concluded that Darc plays a role in modulating the early inflammatory response to bone fracture and subsequent cartilage formation. However, the early cartilage formation was not translated with an early bone formation at the fracture site in Darc-KO compared to WT mice.

Dataset Information

Erythrocyte Duffy antigen receptor for chemokines (DARC): diagnostic and therapeutic implications in atherosclerotic cardiovascular disease.

Publications

Erythrocyte Duffy antigen receptor for chemokines (DARC): diagnostic and therapeutic implications in atherosclerotic cardiovascular disease.

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