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The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity

Nature Immunology volume 10, pages 101–108 (2009)Cite this article

An Erratum to this article was published on 01 February 2009

This article has been updated

Abstract

The Duffy antigen receptor for chemokines (DARC) belongs to a family of 'silent' heptahelical chemokine receptors that do not couple to G proteins and fail to transmit measurable intracellular signals. DARC binds most inflammatory chemokines and is prominently expressed on venular endothelial cells, where its function has remained contentious. Here we show that DARC, like other silent receptors, internalized chemokines but did not effectively scavenge them. Instead, DARC mediated chemokine transcytosis, which led to apical retention of intact chemokines and more leukocyte migration across monolayers expressing DARC. Mice overexpressing DARC on blood vessel endothelium had enhanced chemokine-induced leukocyte extravasation and contact-hypersensitivity reactions. Thus, interactions of chemokines with DARC support their activity on apposing leukocytes in vitro and in vivo.

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Figure 1: Colocalization of DARC and CXCL8 in venular endothelial cells in human skin.
Figure 2: DARC immunoreactivity in MDCK-DARC monolayers.
Figure 3: Chemokine transport by DARC across MDCK-DARC monolayers.
Figure 4: Chemokine degradation by MDCK cells expressing DARC or D6.
Figure 5: Chemokine transport by DARC across HUVEC-DARC monolayers.
Figure 6: CCL2-induced monocyte migration across MDCK cells and HUVECs.
Figure 7: Recruitment of neutrophils into chemokine injection sites in mDARCtg and wild-type mice.
Figure 8: Acute CHS reaction to oxazolone in mDARCtg and wild-type mice.

Change history

  • 16 January 2009

    NOTE: In the version of this article initially published, the images in Fig. 2c,e were truncated. Intact images have replaced those versions. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M. Uchikawa (Japanese Red Cross) for anti-DARC; J.S. Lee (University of Pittsburgh) and J.S. Rhim (Uniformed Services University of the Health Sciences) for HUVECs transfected with DARC or empty vector; G. Posthuma (Utrecht University) for colloidal gold–conjugated protein A; S. Huber for genotyping; and M. Hahn and W. Höllriegl for husbandry. Supported by the European Union Sixth Framework Programme (LSHB-CT-2005-518167 to M.P., L.M., P.B., G.J.G. and A.Ro.), Deutsche Forschungsgemeinschaft (SE 888/4-1 to S.S.) and the Else-Kröner Fresenius Stiftung (to S.S.).

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Authors and Affiliations

  1. Experimental Pathology, Novartis Institutes for BioMedical Research, Vienna, A-1230, Austria

    Monika Pruenster, Liesbeth Mudde, Paula Bombosi, Svetla Dimitrova, Marion Zsak, Jim Middleton & Antal Rot

  2. Medical School, Keele University, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, SY10 7AG, UK

    Jim Middleton

  3. Department of Veterans Affairs and Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    Ann Richmond

  4. Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, G12 8TA, UK

    Gerard J Graham & Robert J B Nibbs

  5. Medizinische Poliklinik, University of Munich, Munich, D-80337, Germany

    Stephan Segerer

  6. Clinic for Nephrology, University of Zurich, Zurich CH-8091, Switzerland.,

    Stephan Segerer

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Contributions

M.P., L.M. and P.B. designed and did experiments, analyzed data and contributed to the preparation of the manuscript; S.D., M.Z. and J.M. designed and did experiments and analyzed data; A.Ri., G.J.G., S.S. and R.J.B.N. provided critical material and contributed to data analysis; and A.Ro. directed the research, designed experiments, analyzed data and wrote the manuscript.

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Correspondence to Antal Rot.

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Competing interests

At the time of this study, M.P., L.M., P.B., S.D., M.Z. and A.Ro. were employees of the Novartis Institutes for BioMedical Research, Vienna.

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Pruenster, M., Mudde, L., Bombosi, P. et al. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nat Immunol 10, 101–108 (2009). https://doi.org/10.1038/ni.1675

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