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.

Procoagulant and proinflammatory effects of red blood cells on lipopolysaccharide‐stimulated monocytes

“…As shown in Fig. B, DARC‐null RBCs failed to potentiate murine monocyte TFa triggered by LPS, suggesting that RBCs likely exert their effect via DARC‐bound chemokines, of which MCP‐1 is a substantial constituent . We then examined the contribution of DARC to the overall TF response of blood monocytes under severe inflammatory conditions: in a model of LPS‐induced endotoxemia, DARC‐null mice exhibited a highly significant, ~30% decrease in the induction of TF‐positive monocytic cells compared with WT mice (Fig.…”

Chemokines and atherosclerosis: focus on the CX3CL1/CX3CR1 pathway

“…Chemokine receptor CCX-CKR is a scavenger of CCR7 ligand chemokines, while D6 is considered to be a chemokine scavenger for pro-inflammatory CC chemokines [10] . DARC is a decoy receptor for both CC and CXC motif chemokines while no data exist on its affinity for CX3C and XC chemokines [11] .…”

Duffy antigen receptor genetic variant and the association with Interleukin 8 levels

“…DARC is expressed on erythrocytes and postcapillary venular endothelial cells (ECs), the primary site of leukocyte transmigration in most tissues [16]. On the surface of erythrocytes, DARC works as a ''chemokine neutralizer'' by clearing circulating chemokines from the sites of overproduction [17].…”

“…It internalizes chemokines, but does not scavenge thereby supporting their promigratory function [18]. DARC expressed on ECs establishes a functional pro-migratory chemokine pattern accessible to the circulating leukocytes [16]. Further, it modulates inflammation and angiogenesis in cancer, sepsis and autoimmune diseases [19,20].…”

“…In CVD, DARC on ECs may play a role in the earliest steps of atherosclerosis, through promoting accumulation and migration of circulating leukocytes into the intima of the vessel wall [23]. In the late stages of the atherosclerotic process, DARC in erythrocytes could potentially function as a cellular regulator of the local inflammatory processes within the plaque and working as a bidirectional reservoir for IL8 [16,24,25]. In fact, erythrocyte membranes are found in the necrotic core of advanced coronary atheromas and correlate with the size of necrotic core that may prompt the risk of plaque vulnerability [26].…”