Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Atypical chemokine receptors in the immune system

Nature Reviews Immunology (2024)Cite this article

Subjects

Abstract

Leukocyte migration is a fundamental component of innate and adaptive immune responses as it governs the recruitment and localization of these motile cells, which is crucial for immune cell priming, effector functions, memory responses and immune regulation. This complex cellular trafficking system is controlled to a large extent via highly regulated production of secreted chemokines and the restricted expression of their membrane-tethered G-protein-coupled receptors. The activity of chemokines and their receptors is also regulated by a subfamily of molecules known as atypical chemokine receptors (ACKRs), which are chemokine receptor-like molecules that do not couple to the classical signalling pathways that promote cell migration in response to chemokine ligation. There has been a great deal of progress in understanding the biology of these receptors and their functions in the immune system in the past decade. Here, we describe the contribution of the various ACKRs to innate and adaptive immune responses, focussing specifically on recent progress. This includes recent findings that have defined the role for ACKRs in sculpting extracellular chemokine gradients, findings that broaden the spectrum of chemokine ligands recognized by these receptors, candidate new additions to ACKR family, and our increasing understanding of the role of these receptors in shaping the migration of innate and adaptive immune cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Atypical chemokine receptors.
Fig. 2: Ligand binding profiles of human atypical chemokine receptors.
Fig. 3: Putative new additions to the atypical chemokine receptor family.
Fig. 4: ACKR4 shapes chemokine gradients for dendritic cell and T cell migration.
Fig. 5: Atypical chemokine receptors regulate neutrophil trafficking.

Similar content being viewed by others

References

  1. Bachelerie, F. et al. New nomenclature for atypical chemokine receptors. Nat. Immunol. 15, 207–208 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Nibbs, R. J. B. & Graham, G. J. Immune regulation by atypical chemokine receptors. Nat. Rev. Immunol. 13, 815–829 (2013).

    Article  PubMed  Google Scholar 

  3. Melgrati, S. et al. Atlas of the anatomical localization of atypical chemokine receptors in healthy mice. PLoS Biol. 21, e3002111 (2023). This study used novel GPR182 reporter mice and other existing ACKR reporter mice and chimeric tagged chemokines to comprehensively identify the distribution pattern of ACKRs throughout the body.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rajagopal, S. et al. β-Arrestin- but not G protein-mediated signaling by the ‘decoy’ receptor CXCR7. Proc. Natl Acad. Sci. USA 107, 628–632 (2010).

    Article  PubMed  Google Scholar 

  5. Hoffmann, F. et al. Rapid uptake and degradation of CXCL12 depend on CXCR7 carboxyl-terminal serine/threonine residues. J. Biol. Chem. 287, 28362–28377 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Galliera, E. et al. beta-Arrestin-dependent constitutive internalization of the human chemokine decoy receptor D6. J. Biol. Chem. 279, 25590–25597 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Watts, A. O. et al. β-Arrestin recruitment and G protein signaling by the atypical human chemokine decoy receptor CCX-CKR. J. Biol. Chem. 288, 7169–7181 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nguyen, H. T. et al. CXCR7: a β-arrestin-biased receptor that potentiates cell migration and recruits β-arrestin2 exclusively through Gβγ subunits and GRK2. Cell Biosci. 10, 134 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Weber, M. et al. The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines. Mol. Biol. Cell 15, 2492–2508 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McCulloch, C. V. et al. Multiple roles for the C-terminal tail of the chemokine scavenger D6. J. Biol. Chem. 283, 7972–7982 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Canals, M. et al. Ubiquitination of CXCR7 controls receptor trafficking. PLoS ONE 7, e34192 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Comerford, I., Milasta, S., Morrow, V., Milligan, G. & Nibbs, R. The chemokine receptor CCX-CKR mediates effective scavenging of CCL19 in vitro. Eur. J. Immunol. 36, 1904–1916 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Torossian, F. et al. CXCR7 participates in CXCL12-induced CD34+ cell cycling through β-arrestin-dependent Akt activation. Blood 123, 191–202 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Matti, C. et al. ACKR4 recruits GRK3 prior to β-arrestins but can scavenge chemokines in the absence of β-arrestins. Front. Immunol. 11, 720 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Saaber, F. et al. ACKR3 regulation of neuronal migration requires ACKR3 phosphorylation, but not β-arrestin. Cell Rep. 26, 1473–1488.e9 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Montpas, N. et al. Ligand-specific conformational transitions and intracellular transport are required for atypical chemokine receptor 3-mediated chemokine scavenging. J. Biol. Chem. 293, 893–905 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Schafer, C. T., Chen, Q., Tesmer, J. J. G. & Handel, T. M. Atypical chemokine receptor 3 ‘senses’ CXC chemokine receptor 4 activation through GPCR kinase phosphorylation. Mol. Pharmacol. https://doi.org/10.1124/molpharm.123.000710 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zarca, A. et al. Differential involvement of ACKR3 C-tail in β-arrestin recruitment, trafficking and internalization. Cells 10, 618 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mackie, D. I. et al. RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis. Proc. Natl Acad. Sci. USA 116, 24093–24099 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Borroni, E. M. et al. β-Arrestin-dependent activation of the cofilin pathway is required for the scavenging activity of the atypical chemokine receptor D6. Sci. Signal. 6, ra30 (2013).

    Article  Google Scholar 

  21. Vacchini, A. et al. Control of cytoskeletal dynamics by β-arrestin1/myosin Vb signaling regulates endosomal sorting and scavenging activity of the atypical chemokine receptor ACKR2. Vaccines 8, 542 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Décaillot, F. M. et al. CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration. J. Biol. Chem. 286, 32188–32197 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Levoye, A., Balabanian, K., Baleux, F., Bachelerie, F. & Lagane, B. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood 113, 6085–6093 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Odemis, V. et al. The presumed atypical chemokine receptor CXCR7 signals through G(i/o) proteins in primary rodent astrocytes and human glioma cells. Glia 60, 372–381 (2012).

    Article  PubMed  Google Scholar 

  25. Fumagalli, A. et al. The atypical chemokine receptor 3 interacts with connexin 43 inhibiting astrocytic gap junctional intercellular communication. Nat. Commun. 11, 4855 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sierro, F. et al. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc. Natl Acad. Sci. USA 104, 14759–14764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gerrits, H. et al. Early postnatal lethality and cardiovascular defects in CXCR7-deficient mice. Genesis 46, 235–245 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Yu, S., Crawford, D., Tsuchihashi, T., Behrens, T. W. & Srivastava, D. The chemokine receptor CXCR7 functions to regulate cardiac valve remodeling. Dev. Dyn. 240, 384–393 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gustavsson, M. et al. Structural basis of ligand interaction with atypical chemokine receptor 3. Nat. Commun. 8, 14135 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yen, Y.-C. et al. Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias. Sci. Adv. 8, eabn8063 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kleist, A. B. et al. Conformational selection guides β-arrestin recruitment at a biased G protein-coupled receptor. Science 377, 222–228 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Thiriot, A. et al. Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues. BMC Biol. 15, 45 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Takatsuka, S., Sekiguchi, A., Tokunaga, M., Fujimoto, A. & Chiba, J. Generation of a panel of monoclonal antibodies against atypical chemokine receptor CCX-CKR by DNA immunization. J. Pharmacol. Toxicol. Methods 63, 250–257 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Bobkov, V. et al. Antibodies targeting chemokine receptors CXCR4 and ACKR3. Mol. Pharmacol. 96, 753–764 (2019).

    Article  PubMed  Google Scholar 

  35. Hansell, C. A. H. et al. Analysis of lung stromal expression of the atypical chemokine receptor ACKR2 reveals unanticipated expression in murine blood endothelial cells. Eur. J. Immunol. 50, 666–675 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hur, J. et al. CD82/KAI1 maintains the dormancy of long-term hematopoietic stem cells through interaction with DARC-expressing macrophages. Cell Stem Cell 18, 508–521 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Rot, A. et al. Murine bone marrow macrophages and human monocytes do not express atypical chemokine receptor 1. Cell Stem Cell 29, 1013–1015 (2022).

    Article  CAS  PubMed  Google Scholar 

  38. Neote, K., Mak, J. Y., Kolakowski, L. F. & Schall, T. J. Functional and biochemical analysis of the cloned Duffy antigen: identity with the red blood cell chemokine receptor. Blood 84, 44–52 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Horuk, R. et al. Expression of chemokine receptors by subsets of neurons in the central nervous system. J. Immunol. 158, 2882–2890 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Madigan, J. et al. Chemokine scavenger D6 is expressed by trophoblasts and aids the survival of mouse embryos transferred into allogeneic recipients. J. Immunol. 184, 3202–3212 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Teoh, P. J. et al. Atypical chemokine receptor ACKR2 mediates chemokine scavenging by primary human trophoblasts and can regulate fetal growth, placental structure, and neonatal mortality in mice. J. Immunol. 193, 5218–5228 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Thomson, C. A. et al. Expression of the atypical chemokine receptor ACKR4 identifies a novel population of intestinal submucosal fibroblasts that preferentially expresses endothelial cell regulators. J. Immunol. 201, 215–229 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Bastow, C. R. et al. Scavenging of soluble and immobilized CCL21 by ACKR4 regulates peripheral dendritic cell emigration. Proc. Natl Acad. Sci. USA 118, e2025763118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang, M. et al. Inhibition of fibroblast IL-6 production by ACKR4 deletion alleviates cardiac remodeling after myocardial infarction. Biochem. Biophys. Res. Commun. 547, 139–147 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. Hansell, C. A. H. et al. Universal expression and dual function of the atypical chemokine receptor D6 on innate-like B cells in mice. Blood 117, 5413–5424 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Ford, L. B. et al. Characterization of conventional and atypical receptors for the chemokine CCL2 on mouse leukocytes. J. Immunol. 193, 400–411 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. McKimmie, C. S. et al. Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1. J. Immunol. 181, 3353–3363 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Radice, E. et al. Marginal zone formation requires ACKR3 expression on B cells. Cell Rep. 32, 107951 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Kara, E. E. et al. Atypical chemokine receptor 4 shapes activated B cell fate. J. Exp. Med. 215, 801–813 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kealy, L. et al. The histone methyltransferase DOT1L is essential for humoral immune responses. Cell Rep. 33, 108504 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Lau, S. et al. A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration. Nat. Cell Biol. 22, 266–273 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Klei, T. R. L. et al. Differential interaction between DARC and SDF-1 on erythrocytes and their precursors. Sci. Rep. 9, 16245 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gutjahr, J. C. et al. The dimeric form of CXCL12 binds to atypical chemokine receptor 1. Sci. Signal. 14, eabc9012 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Drury, L. J. et al. Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways. Proc. Natl Acad. Sci. USA 108, 17655–17660 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nagasawa, T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Nibbs, R. J., Wylie, S. M., Yang, J., Landau, N. R. & Graham, G. J. Cloning and characterization of a novel promiscuous human beta-chemokine receptor D6. J. Biol. Chem. 272, 32078–32083 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Bonecchi, R. et al. Differential recognition and scavenging of native and truncated macrophage-derived chemokine (macrophage-derived chemokine/CC chemokine ligand 22) by the D6 decoy receptor. J. Immunol. 172, 4972–4976 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Fra, A. M. et al. Cutting edge: scavenging of inflammatory CC chemokines by the promiscuous putatively silent chemokine receptor D6. J. Immunol. 170, 2279–2282 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Jamieson, T. et al. The chemokine receptor D6 limits the inflammatory response in vivo. Nat. Immunol. 6, 403–411 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Martinez de la Torre, Y. et al. Increased inflammation in mice deficient for the chemokine decoy receptor D6. Eur. J. Immunol. 35, 1342–1346 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Lee, K. M. et al. D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion. Blood 118, 6220–6229 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wilson, G. J. et al. Chemokine receptors coordinately regulate macrophage dynamics and mammary gland development. Dev. Camb. Engl. 147, dev187815 (2020).

    CAS  Google Scholar 

  63. Wilson, G. J. et al. Atypical chemokine receptor ACKR2 controls branching morphogenesis in the developing mammary gland. Dev. Camb. Engl. 144, 74–82 (2017).

    CAS  Google Scholar 

  64. Chevigné, A. et al. CXCL10 is an agonist of the CC family chemokine scavenger receptor ACKR2/D6. Cancers 13, 1054 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Groom, J. R. & Luster, A. D. CXCR3 in T cell function. Exp. Cell Res. 317, 620–631 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Prizant, H. et al. CXCL10+ peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter. Cell Rep. 36, 109523 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Duckworth, B. C. et al. Effector and stem-like memory cell fates are imprinted in distinct lymph node niches directed by CXCR3 ligands. Nat. Immunol. 22, 434–448 (2021).

    Article  CAS  PubMed  Google Scholar 

  68. Burns, J. M. et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J. Exp. Med. 203, 2201–2213 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Klein, K. R. et al. Decoy receptor CXCR7 modulates adrenomedullin-mediated cardiac and lymphatic vascular development. Dev. Cell 30, 528–540 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Humpert, M.-L., Pinto, D., Jarrossay, D. & Thelen, M. CXCR7 influences the migration of B cells during maturation. Eur. J. Immunol. 44, 694–705 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Sánchez-Alcañiz, J. A. et al. Cxcr7 controls neuronal migration by regulating chemokine responsiveness. Neuron 69, 77–90 (2011).

    Article  PubMed  Google Scholar 

  72. Schönemeier, B. et al. Regional and cellular localization of the CXCl12/SDF-1 chemokine receptor CXCR7 in the developing and adult rat brain. J. Comp. Neurol. 510, 207–220 (2008).

    Article  PubMed  Google Scholar 

  73. Humpert, M.-L. et al. Complementary methods provide evidence for the expression of CXCR7 on human B cells. Proteomics 12, 1938–1948 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Balabanian, K. et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J. Biol. Chem. 280, 35760–35766 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Boldajipour, B. et al. Control of chemokine-guided cell migration by ligand sequestration. Cell 132, 463–473 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Dambly-Chaudière, C., Cubedo, N. & Ghysen, A. Control of cell migration in the development of the posterior lateral line: antagonistic interactions between the chemokine receptors CXCR4 and CXCR7/RDC1. BMC Dev. Biol. 7, 23 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Berahovich, R. D. et al. Endothelial expression of CXCR7 and the regulation of systemic CXCL12 levels. Immunology 141, 111–122 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Alampour-Rajabi, S. et al. MIF interacts with CXCR7 to promote receptor internalization, ERK1/2 and ZAP-70 signaling, and lymphocyte chemotaxis. FASEB J. 29, 4497–4511 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Chatterjee, M. et al. Macrophage migration inhibitory factor limits activation-induced apoptosis of platelets via CXCR7-dependent Akt signaling. Circ. Res. 115, 939–949 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Szpakowska, M. et al. Human herpesvirus 8-encoded chemokine vCCL2/vMIP-II is an agonist of the atypical chemokine receptor ACKR3/CXCR7. Biochem. Pharmacol. 114, 14–21 (2016).

    Article  CAS  PubMed  Google Scholar 

  81. Meyrath, M. et al. The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nat. Commun. 11, 3033 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Szpakowska, M. et al. The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7. Signal Transduct. Target. Ther. 6, 209 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ikeda, Y., Kumagai, H., Skach, A., Sato, M. & Yanagisawa, M. Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior. Cell 155, 1323–1336 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Meyrath, M. et al. Proadrenomedullin N-terminal 20 peptides (PAMPs) are agonists of the chemokine scavenger receptor ACKR3/CXCR7. ACS Pharmacol. Transl. Sci. 4, 813–823 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sigmund, E. C. et al. Reassessing the adrenomedullin scavenging function of ACKR3 in lymphatic endothelial cells. PLoS ONE 18, e0285597 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zabel, B. A. et al. Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J. Immunol. 183, 3204–3211 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Gosling, J. et al. Cutting edge: identification of a novel chemokine receptor that binds dendritic cell- and T cell-active chemokines including ELC, SLC, and TECK. J. Immunol. 164, 2851–2856 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Townson, J. R. & Nibbs, R. J. B. Characterization of mouse CCX-CKR, a receptor for the lymphocyte-attracting chemokines TECK/mCCL25, SLC/mCCL21 and MIP-3beta/mCCL19: comparison to human CCX-CKR. Eur. J. Immunol. 32, 1230–1241 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Misslitz, A. et al. Thymic T cell development and progenitor localization depend on CCR7. J. Exp. Med. 200, 481–491 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ueno, T. et al. CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J. Exp. Med. 200, 493–505 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kurobe, H. et al. CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 24, 165–177 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Benz, C., Heinzel, K. & Bleul, C. C. Homing of immature thymocytes to the subcapsular microenvironment within the thymus is not an absolute requirement for T cell development. Eur. J. Immunol. 34, 3652–3663 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Braun, A. et al. Afferent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration. Nat. Immunol. 12, 879–887 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Tal, O. et al. DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J. Exp. Med. 208, 2141–2153 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ohl, L. et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Förster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).

    Article  PubMed  Google Scholar 

  97. Warnock, R. A. et al. The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer’s patch high endothelial venules. J. Exp. Med. 191, 77–88 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kunkel, E. J. et al. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J. Exp. Med. 192, 761–768 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Breitfeld, D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1552 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Förster, R. et al. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996).

    Article  PubMed  Google Scholar 

  101. Ulvmar, M. H. et al. The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes. Nat. Immunol. 15, 623–630 (2014). This study demonstrates that ACKR is expressed on ceiling lymphatic vessels in the lymph node subcapsular sinus and governs the formation of interfollicular extracellular CCL21 gradients that are required for efficient migration of DCs from the lymph node subcapsular sinus to the T cell zone.

    Article  CAS  PubMed  Google Scholar 

  102. Bryce, S. A. et al. ACKR4 on stromal cells scavenges CCL19 to enable CCR7-dependent trafficking of APCs from inflamed skin to lymph nodes. J. Immunol. 196, 3341–3353 (2016). This study is, to our knowledge, the first to determine that ACKR4 in the skin modulates CCR7 ligand chemokines and is required for efficient recruitment of DCs out of the skin.

    Article  CAS  PubMed  Google Scholar 

  103. Heinzel, K., Benz, C. & Bleul, C. C. A silent chemokine receptor regulates steady-state leukocyte homing in vivo. Proc. Natl Acad. Sci. USA 104, 8421–8426 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Rode, I. & Boehm, T. Regenerative capacity of adult cortical thymic epithelial cells. Proc. Natl Acad. Sci. USA 109, 3463–3468 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Bunting, M. D. et al. CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity. Blood 121, 118–128 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Comerford, I. et al. An immune paradox: how can the same chemokine axis regulate both immune tolerance and activation?: CCR6/CCL20: a chemokine axis balancing immunological tolerance and inflammation in autoimmune disease. BioEssays 32, 1067–1076 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Schutyser, E., Struyf, S. & Van Damme, J. The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 14, 409–426 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Matti, C. et al. CCL20 is a novel ligand for the scavenging atypical chemokine receptor 4. J. Leukoc. Biol. 107, 1137–1154 (2020).

    Article  CAS  PubMed  Google Scholar 

  109. Meyrath, M., Reynders, N., Uchański, T., Chevigné, A. & Szpakowska, M. Systematic reassessment of chemokine-receptor pairings confirms CCL20 but not CXCL13 and extends the spectrum of ACKR4 agonists to CCL22. J. Leukoc. Biol. 109, 373–376 (2021).

    Article  CAS  PubMed  Google Scholar 

  110. Reboldi, A. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat. Immunol. 10, 514–523 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Villares, R. et al. CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T-cell recruitment to target tissues. Eur. J. Immunol. 39, 1671–1681 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Lin, Y.-L., Ip, P.-P. & Liao, F. CCR6 deficiency impairs IgA production and dysregulates antimicrobial peptide production, altering the intestinal flora. Front. Immunol. 8, 805 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Reimer, D. et al. Early CCR6 expression on B cells modulates germinal centre kinetics and efficient antibody responses. Immunol. Cell Biol. 95, 33–41 (2017).

    Article  CAS  PubMed  Google Scholar 

  114. Yamamoto, J. et al. Differential expression of the chemokine receptors by the Th1- and Th2-type effector populations within circulating CD4+ T cells. J. Leukoc. Biol. 68, 568–574 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Acosta-Rodriguez, E. V. et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 8, 639–646 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Iellem, A. et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J. Exp. Med. 194, 847–853 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Soler, D., Humphreys, T. L., Spinola, S. M. & Campbell, J. J. CCR4 versus CCR10 in human cutaneous TH lymphocyte trafficking. Blood 101, 1677–1682 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K. & Spits, H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat. Immunol. 10, 864–871 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Mariani, M., Lang, R., Binda, E., Panina-Bordignon, P. & D’Ambrosio, D. Dominance of CCL22 over CCL17 in induction of chemokine receptor CCR4 desensitization and internalization on human Th2 cells. Eur. J. Immunol. 34, 231–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Verkaar, F. et al. Chemokine cooperativity is caused by competitive glycosaminoglycan binding. J. Immunol. 192, 3908–3914 (2014).

    Article  CAS  PubMed  Google Scholar 

  121. Davenport, A. P. et al. International union of basic and clinical pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65, 967–986 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bachelerie, F. et al. An atypical addition to the chemokine receptor nomenclature: IUPHAR review 15. Br. J. Pharmacol. 172, 3945–3949 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kapas, S., Catt, K. J. & Clark, A. J. Cloning and expression of cDNA encoding a rat adrenomedullin receptor. J. Biol. Chem. 270, 25344–25347 (1995).

    Article  CAS  PubMed  Google Scholar 

  124. Kennedy, S. P. et al. Expression of the rat adrenomedullin receptor or a putative human adrenomedullin receptor does not correlate with adrenomedullin binding or functional response. Biochem. Biophys. Res. Commun. 244, 832–837 (1998).

    Article  CAS  PubMed  Google Scholar 

  125. Kwon, H.-B. et al. The orphan G-protein coupled receptor 182 is a negative regulator of definitive hematopoiesis through leukotriene B4 signaling. ACS Pharmacol. Transl. Sci. 3, 676–689 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Le Mercier, A. et al. GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis. Proc. Natl Acad. Sci. USA 118, e2021596118 (2021). This study is, to our knowledge, the first to identify that GPR182 is an atypical chemokine receptor that regulates levels of CXCL10, CXCL12 and CXCL13 in vivo and influences HSC homoeostasis.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Torphy, R. J. et al. GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models. Nat. Commun. 13, 97 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Melgrati, S. et al. GPR182 is a broadly scavenging atypical chemokine receptor influencing T-independent immunity. Front. Immunol. 14, 1242531 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Biber, K., Zuurman, M. W., Homan, H. & Boddeke, H. W. G. M. Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8. J. Leukoc. Biol. 74, 243–251 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Leick, M. et al. CCL19 is a specific ligand of the constitutively recycling atypical human chemokine receptor CRAM-B. Immunology 129, 536–546 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Catusse, J. et al. Role of the atypical chemoattractant receptor CRAM in regulating CCL19 induced CCR7 responses in B-cell chronic lymphocytic leukemia. Mol. Cancer 9, 297 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Su, Z. et al. Studies with neutralizing antibodies suggest CXCL8-mediated neutrophil activation is independent of C-C motif chemokine receptor-like 2 (CCRL2) ligand binding function. PLoS ONE 18, e0280590 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zabel, B. A. et al. Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis. J. Exp. Med. 205, 2207–2220 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Fischer, T. F. & Beck-Sickinger, A. G. Chemerin — exploring a versatile adipokine. Biol. Chem. 403, 625–642 (2022).

    Article  CAS  PubMed  Google Scholar 

  135. Al Delbany, D. et al. Expression of CCRL2 inhibits tumor growth by concentrating chemerin and inhibiting neoangiogenesis. Cancers 13, 5000 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. De Henau, O. et al. Signaling properties of chemerin receptors CMKLR1, GPR1 and CCRL2. PLoS ONE 11, e0164179 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Degroot, G.-N., Lepage, V., Parmentier, M. & Springael, J.-Y. The atypical chemerin receptor GPR1 displays different modes of interaction with β-arrestins in humans and mice with important consequences on subcellular localization and trafficking. Cells 11, 1037 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Del Prete, A. et al. The atypical receptor CCRL2 is required for CXCR2-dependent neutrophil recruitment and tissue damage. Blood 130, 1223–1234 (2017).

    Article  PubMed  Google Scholar 

  139. Li, X. X., Lee, J. D., Kemper, C. & Woodruff, T. M. The complement receptor C5aR2: a powerful modulator of innate and adaptive immunity. J. Immunol. 202, 3339–3348 (2019).

    Article  CAS  PubMed  Google Scholar 

  140. Chen, J. et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19, 541–555 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lev, S. et al. Identification of a novel family of targets of PYK2 related to Drosophila retinal degeneration B (rdgB) protein. Mol. Cell. Biol. 19, 2278–2288 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Zeng, W. et al. CCL18 signaling from tumor-associated macrophages activates fibroblasts to adopt a chemoresistance-inducing phenotype. Oncogene 42, 224–237 (2023).

    Article  CAS  PubMed  Google Scholar 

  143. Jiang, X. et al. CCL18-NIR1 promotes oral cancer cell growth and metastasis by activating the JAK2/STAT3 signaling pathway. BMC Cancer 20, 632 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Campanella, G. S. V., Colvin, R. A. & Luster, A. D. CXCL10 can inhibit endothelial cell proliferation independently of CXCR3. PLoS ONE 5, e12700 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Korniejewska, A., McKnight, A. J., Johnson, Z., Watson, M. L. & Ward, S. G. Expression and agonist responsiveness of CXCR3 variants in human T lymphocytes. Immunology 132, 503–515 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Lasagni, L. et al. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. J. Exp. Med. 197, 1537–1549 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Struyf, S. et al. Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3. Blood 117, 480–488 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gray, A. L. et al. Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors. Cell Rep. 42, 111930 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. D’Uonnolo, G. et al. The extended N-terminal domain confers atypical chemokine receptor properties to CXCR3-B. Front. Immunol. 13, 868579 (2022). This study identifies the atypical chemokine receptor-like properties of CXCR3-B, determining that its extended N-terminus prevents G protein coupling and modifies its subcellular localization.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Smith, J. S. et al. C-X-C motif chemokine receptor 3 splice variants differentially activate beta-arrestins to regulate downstream signaling pathways. Mol. Pharmacol. 92, 136–150 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sfriso, P. et al. Epithelial CXCR3-B regulates chemokines bioavailability in normal, but not in Sjogren’s syndrome, salivary glands. J. Immunol. 176, 2581–2589 (2006).

    Article  CAS  PubMed  Google Scholar 

  152. Borroni, E. M., Savino, B., Bonecchi, R. & Locati, M. Chemokines sound the alarmin: the role of atypical chemokine in inflammation and cancer. Semin. Immunol. 38, 63–71 (2018).

    Article  CAS  PubMed  Google Scholar 

  153. Crawford, K. S. & Volkman, B. F. Prospects for targeting ACKR1 in cancer and other diseases. Front. Immunol. 14, 1111960 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Koch, C. & Engele, J. Functions of the CXCL12 receptor ACKR3/CXCR7 — what has been perceived and what has been overlooked. Mol. Pharmacol. 98, 577–585 (2020).

    Article  CAS  PubMed  Google Scholar 

  155. Gowhari Shabgah, A. et al. The role of atypical chemokine receptor D6 (ACKR2) in physiological and pathological conditions; friend, foe, or both? Front. Immunol. 13, 861931 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Tavares, L. P. et al. ACKR2 contributes to pulmonary dysfunction by shaping CCL5:CCR5-dependent recruitment of lymphocytes during influenza A infection in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 318, L655–L670 (2020).

    Article  CAS  PubMed  Google Scholar 

  157. Weber, M. et al. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339, 328–332 (2013). This seminal study provides the first direct visualization of an extracellular chemokine gradient, which was shown to govern DC sensing of lymphatic vessels in the skin.

    Article  CAS  PubMed  Google Scholar 

  158. Comerford, I. et al. The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses. Blood 116, 4130–4140 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Jafarnejad, M., Zawieja, D. C., Brook, B. S., Nibbs, R. J. B. & Moore, J. E. A novel computational model predicts key regulators of chemokine gradient formation in lymph nodes and site-specific roles for CCL19 and ACKR4. J. Immunol. 199, 2291–2304 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Friess, M. C. et al. Mechanosensitive ACKR4 scavenges CCR7 chemokines to facilitate T cell de-adhesion and passive transport by flow in inflamed afferent lymphatics. Cell Rep. 38, 110334 (2022). This study demonstrates how ACKR4 regulates chemokine deposition in lymphatic collector vessels and facilitates T cell migration in afferent lymph.

    Article  CAS  PubMed  Google Scholar 

  161. Werth, K. et al. Expression of ACKR4 demarcates the ‘peri-marginal sinus,’ a specialized vascular compartment of the splenic red pulp. Cell Rep. 36, 109346 (2021).

    Article  CAS  PubMed  Google Scholar 

  162. Marchetti, L. et al. ACKR1 favors transcellular over paracellular T‐cell diapedesis across the blood‐brain barrier in neuroinflammation in vitro. Eur. J. Immunol. 52, 161–177 (2022).

    Article  CAS  PubMed  Google Scholar 

  163. Girbl, T. et al. Distinct compartmentalization of the chemokines CXCL1 and CXCL2 and the atypical receptor ACKR1 determine discrete stages of neutrophil diapedesis. Immunity 49, 1062–1076.e6 (2018). This study elegantly determines how ACKR1, CXCL1 and CXCL2 are compartmentalized on endothelial cells to facilitate the stages of neutrophil diapedesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Wang, H. et al. The CXCR7 chemokine receptor promotes B-cell retention in the splenic marginal zone and serves as a sink for CXCL12. Blood 119, 465–468 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Eckert, N., Werth, K., Willenzon, S., Tan, L. & Förster, R. B cell hyperactivation in an Ackr4-deficient mouse strain is not caused by lack of ACKR4 expression. J. Leukoc. Biol. 107, 1155–1166 (2020).

    Article  CAS  PubMed  Google Scholar 

  166. Zhang, Y. et al. Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift. Nat. Commun. 13, 2460 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Merz, L. E. et al. Absolute neutrophil count by Duffy status among healthy Black and African American adults. Blood Adv. 7, 317–320 (2023).

    Article  PubMed  Google Scholar 

  168. Duchene, J. et al. Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis. Nat. Immunol. 18, 753–761 (2017). This study identifies the mechanism that links the absence of ACKR1 on erythroid cells with neutropenia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Charles, B. A. et al. Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia. PLoS ONE 13, e0194400 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Miyabe, Y., Miyabe, C., Mani, V., Mempel, T. R. & Luster, A. D. Atypical complement receptor C5aR2 transports C5a to initiate neutrophil adhesion and inflammation. Sci. Immunol. 4, eaav5951 (2019).

    Article  CAS  PubMed  Google Scholar 

  171. Martin, C. et al. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19, 583–593 (2003).

    Article  CAS  PubMed  Google Scholar 

  172. Barkaway, A. et al. Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage. Immunity 54, 1494–1510.e7 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Rot, A. et al. Cell-autonomous regulation of neutrophil migration by the D6 chemokine decoy receptor. J. Immunol. 190, 6450–6456 (2013).

    Article  CAS  PubMed  Google Scholar 

  174. Massara, M. et al. ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity. Nat. Commun. 9, 676 (2018). This study identifies the important contribution of ACKR2 expressed by haematopoietic progenitors in the release of neutrophils in the context of breast cancer and melanoma.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Pashover-Schallinger, E. et al. The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation. FASEB J. 26, 3891–3900 (2012).

    Article  CAS  PubMed  Google Scholar 

  176. Aswad, M., Assi, S., Schif-Zuck, S. & Ariel, A. CCL5 promotes resolution-phase macrophage reprogramming in concert with the atypical chemokine receptor D6 and apoptotic polymorphonuclear cells. J. Immunol. 199, 1393–1404 (2017).

    Article  CAS  PubMed  Google Scholar 

  177. Heesen, M. et al. Cloning and chromosomal mapping of an orphan chemokine receptor: mouse RDC1. Immunogenetics 47, 364–370 (1998).

    Article  CAS  PubMed  Google Scholar 

  178. Ngamsri, K.-C. et al. The pivotal role of CXCR7 in stabilization of the pulmonary epithelial barrier in acute pulmonary inflammation. J. Immunol. 198, 2403–2413 (2017).

    Article  CAS  PubMed  Google Scholar 

  179. Cruz-Orengo, L. et al. CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. J. Exp. Med. 208, 327–339 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Ameti, R. et al. Characterization of a chimeric chemokine as a specific ligand for ACKR3. J. Leukoc. Biol. 104, 391–400 (2018).

    Article  CAS  PubMed  Google Scholar 

  181. Konrad, F. M., Meichssner, N., Bury, A., Ngamsri, K.-C. & Reutershan, J. Inhibition of SDF-1 receptors CXCR4 and CXCR7 attenuates acute pulmonary inflammation via the adenosine A2B-receptor on blood cells. Cell Death Dis. 8, e2832 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Ngamsri, K.-C. et al. CXCR4 and CXCR7 inhibition ameliorates the formation of platelet-neutrophil complexes and neutrophil extracellular traps through Adora2b signaling. Int. J. Mol. Sci. 22, 13576 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Calì, B. et al. Atypical CXCL12 signaling enhances neutrophil migration by modulating nuclear deformability. Sci. Signal. 15, eabk2552 (2022).

    Article  PubMed  Google Scholar 

  184. Gencer, S. et al. Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium. Basic Res. Cardiol. 117, 30 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Peiper, S. C. et al. The Duffy antigen/receptor for chemokines (DARC) is expressed in endothelial cells of Duffy negative individuals who lack the erythrocyte receptor. J. Exp. Med. 181, 1311–1317 (1995).

    Article  CAS  PubMed  Google Scholar 

  186. Szabo, M. C., Soo, K. S., Zlotnik, A. & Schall, T. J. Chemokine class differences in binding to the Duffy antigen-erythrocyte chemokine receptor. J. Biol. Chem. 270, 25348–25351 (1995).

    Article  CAS  PubMed  Google Scholar 

  187. Gardner, L., Patterson, A. M., Ashton, B. A., Stone, M. A. & Middleton, J. The human Duffy antigen binds selected inflammatory but not homeostatic chemokines. Biochem. Biophys. Res. Commun. 321, 306–312 (2004).

    Article  CAS  PubMed  Google Scholar 

  188. Spaan, A. N. et al. Staphylococcus aureus targets the Duffy antigen receptor for chemokines (DARC) to lyse erythrocytes. Cell Host Microbe 18, 363–370 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Bolton, M. J. & Garry, R. F. Sequence similarity between the erythrocyte binding domain 1 of the Plasmodium vivax Duffy binding protein and the V3 loop of HIV-1 strain MN reveals binding residues for the Duffy antigen receptor for chemokines. Virol. J. 8, 45 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Chitnis, C. E. & Miller, L. H. Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion. J. Exp. Med. 180, 497–506 (1994).

    Article  CAS  PubMed  Google Scholar 

  191. Nibbs, R. J., Wylie, S. M., Pragnell, I. B. & Graham, G. J. Cloning and characterization of a novel murine beta chemokine receptor, D6. Comparison to three other related macrophage inflammatory protein-1alpha receptors, CCR-1, CCR-3, and CCR-5. J. Biol. Chem. 272, 12495–12504 (1997).

    Article  CAS  PubMed  Google Scholar 

  192. Nibbs, R. J., Yang, J., Landau, N. R., Mao, J. H. & Graham, G. J. LD78beta, a non-allelic variant of human MIP-1alpha (LD78alpha), has enhanced receptor interactions and potent HIV suppressive activity. J. Biol. Chem. 274, 17478–17483 (1999).

    Article  CAS  PubMed  Google Scholar 

  193. Goncharuk, M. V. et al. Purification of native CCL7 and its functional interaction with selected chemokine receptors. Protein Expr. Purif. 171, 105617 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I.C. is supported by a Senior Research Fellowship from MS Australia.

Author information

Authors and Affiliations

  1. The Chemokine Biology Laboratory, School of Molecular & Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia

    Iain Comerford & Shaun R. McColl

Authors
  1. Iain Comerford
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaun R. McColl
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I.C. contributed to the writing, discussion, review and editing of the manuscript; S.R.McC. contributed to the discussion, review and editing of the manuscript.

Corresponding author

Correspondence to Iain Comerford.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Immunology thanks P. von Hundelshausen, J. Duchene and R. Bonecchi for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Comerford, I., McColl, S.R. Atypical chemokine receptors in the immune system. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01025-5

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41577-024-01025-5

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing