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Inclusion of ACKR5 in the systematic nomenclature of atypical chemokine receptors

Nature Reviews Immunology volume 25, pages 225–226 (2025) Cite this article

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ACKR5 is a scavenger for a broad range of chemokines from the CXC, CC and XC chemokine ligand families, although there are marked differences in the chemokine repertoires of the human and mouse orthologues4,5,6,7,8. It is the only atypical receptor for XCL chemokines, CXCL13 and CCL28, and is the first receptor reported so far for the orphan chemokines CXCL14 and CXCL17 (refs. 6,8). Similarly to ACKR3, ACKR5 also binds non-chemokine ligands, including GPR15L and several endogenous peptides8. ACKR5 is not present on CD45-positive haematopoietic cells but is highly expressed in microvascular and lymphatic endothelial cells across multiple organs4, notably in the venules of the spleen and lymph nodes, where it supports T cell-independent humoral responses7,9. In mouse models, ACKR5 deficiency results in splenomegaly, altered haematopoiesis and causes increased serum chemokine levels, highlighting a role for ACKR5 in maintaining chemokine homeostasis and regulating immune responses4,6,7,9. Interestingly, ACKR5 cooperates with ACKR3 and ACKR4 in regulating serum levels of CXCL12 and CCL19, respectively7. Additionally, ACKR5 is upregulated in melanoma-associated lymphatic endothelial cells, where it scavenges IFNγ-induced chemokines and modulates tumour immunity5.

In summary, these findings underscore crucial roles of ACKR5 in regulating chemokine biology and support its recent inclusion in the ACKR family3. Many aspects of ACKR5 biology remain to be elucidated and future studies will undoubtedly shed new light on its contributions in shaping immune and other responses.

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Fig. 1: ACKR ligand selectivity, expression, function and cross-talk with classical chemokine receptors.
The alternative text for this image may have been generated using AI.

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Authors and Affiliations

  1. Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg

    Martyna Szpakowska & Andy Chevigné

  2. Institute of Cell Biology and Immunology Thurgau (BITG), University of Konstanz, Kreuzlingen, Switzerland

    Daniel F. Legler

  3. Faculty of Biology, University of Konstanz, Konstanz, Germany

    Daniel F. Legler

  4. Theodor Kocher Institute, University of Bern, Bern, Switzerland

    Daniel F. Legler

  5. Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany

    Stefan Offermanns

  6. Cardiopulmonary Institute, Bad Nauheim, Germany

    Stefan Offermanns

  7. Center for Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany

    Stefan Offermanns

  8. German Center for Cardiovascular Research, Partner Site Frankfurt, Bad Nauheim, Germany

    Stefan Offermanns

  9. Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Institute Pasteur-Italia, Rome, Italy

    Silvano Sozzani

  10. Centre for Microvascular Research, William Harvey Research Institute, Queen Mary University of London, London, UK

    Antal Rot

  11. Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland

    Marcus Thelen

Authors
  1. Martyna Szpakowska
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  2. Daniel F. Legler
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  3. Stefan Offermanns
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  4. Silvano Sozzani
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  7. Andy Chevigné
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Correspondence to Andy Chevigné.

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Szpakowska, M., Legler, D.F., Offermanns, S. et al. Inclusion of ACKR5 in the systematic nomenclature of atypical chemokine receptors. Nat Rev Immunol 25, 225–226 (2025). https://doi.org/10.1038/s41577-025-01135-8

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