Abstract
The Duffy Antigen Receptor for Chemokines (DARC) is expressed on erythrocytes and on endothelium of postcapillary venules and splenic sinusoids. Absence of DARC on erythrocytes, but not on endothelium, is referred to as the Duffy negative phenotype and is associated with neutropenia. Here we provide evidence that stromal cell-derived factor 1 (SDF-1), the chemokine that restricts neutrophil precursors to the bone marrow, binds to erythrocyte progenitors in a DARC-dependent manner. Furthermore, we show that SDF-1 binding to DARC is dependent on the conformation of DARC, which gradually changes during erythroid development, resulting in the absence of SDF-1 binding to mature erythrocytes. However, SDF-1 binding to erythrocytes was found to be inducible by pre-treating erythrocytes with IL-8 or with antibodies recognizing specific epitopes on DARC. Taken together, these novel findings identify DARC on erythrocyte precursors as a receptor for SDF-1, which may be of interest in beginning to understand the development of neutropenia in situations where DARC expression is limited.
Highlights
Duffy Antigen Receptor for Chemokines (DARC) is an atypical chemokine receptor that, structurally similar to G-protein coupled receptors, does not signal due to lack of the typical DRYLAIV G-protein-coupling sequence[1]
We found that the most immature CD71high reticulocytes in the circulation, and to a lesser extent CD71low reticulocytes, but not erythrocytes, bind stromal cell-derived factor 1 (SDF-1) (Fig. 1a)
We found that SDF-1 binding to bone marrow reticulocytes was even higher in comparison to reticulocytes and erythrocytes from peripheral blood (Fig. 1c)
Summary
DARC is an atypical chemokine receptor that, structurally similar to G-protein coupled receptors, does not signal due to lack of the typical DRYLAIV G-protein-coupling sequence[1]. Various other chemokines that have previously been described, similar to SDF-1, not to interact with erythrocytes[5], did not bind reticulocytes (Fig. 1d). We suggest that SDF-1 binds to DARC on immature CD71+ reticulocytes and this interaction is lost upon reticulocyte maturation to erythrocytes.
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