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  • Review Article
  • Published:

Immune regulation by atypical chemokine receptors

Nature Reviews Immunology volume 13, pages 815–829 (2013)Cite this article

Subjects

Key Points

  • Leukocyte migration is a central component of all physiological and pathological immune and inflammatory responses. Chemokines, functioning through conventional G protein-coupled chemokine receptors, are the key molecules that are involved in coordinating this process.

  • Atypical chemokine receptors (ACKRs) are structurally related to conventional chemokine receptors but are unable to initiate classical chemokine receptor signalling after ligand binding. This family of chemokine receptors currently has four members: ACKR1 (also known as DARC), ACKR2 (also known as D6), ACKR3 (also known as CXCR7) and ACKR4 (also known as CCRL1).

  • ACKRs use a variety of strategies to regulate chemokines and chemokine-driven responses, including chemokine degradation and transport, and chemokine receptor regulation. Endothelial cells of the lymphatic and blood vasculature are prominent sites of ACKR expression.

  • Studies investigating genetic variation in human ACKRs and the effect of ACKR deficiency in mice and zebrafish have showed that some ACKRs have key developmental and homeostatic functions in the immune system and elsewhere.

  • ACKRs have emerged as important regulators of immune and inflammatory responses, infectious disease, and cancer, and could represent plausible therapeutic targets.

Abstract

Chemokines have fundamental roles in regulating immune and inflammatory responses, primarily through their control of leukocyte migration and localization. The biological functions of chemokines are typically mediated by signalling through G protein-coupled chemokine receptors, but chemokines are also bound by a small family of atypical chemokine receptors (ACKRs), the members of which are unified by their inability to initiate classical signalling pathways after ligand binding. These ACKRs are emerging as crucial regulatory components of chemokine networks in a wide range of developmental, physiological and pathological contexts. In this Review, we discuss the biochemical and immunological properties of ACKRs and the potential unifying themes in this family, and we highlight recent studies that identify novel roles for these molecules in development, homeostasis, inflammatory disease, infection and cancer.

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Figure 1: Chemokine binding profiles of ACKRs.
Figure 2: Cellular functions of ACKRs.
Figure 3: Models for immune and inflammatory functions of ACKRs in vivo.
Figure 4: Roles for ACKRs in cancer.

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Acknowledgements

Work in the authors's laboratories is supported by a programme grant from the UK Medical Research Council. G.J.G. is also the recipient of a Wellcome Trust Senior Investigator Award.

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  1. Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, Scotland, UK

    Robert J. B. Nibbs & Gerard J. Graham

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Nibbs, R., Graham, G. Immune regulation by atypical chemokine receptors. Nat Rev Immunol 13, 815–829 (2013). https://doi.org/10.1038/nri3544

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