A recent Review in this journal by Comerford and McColl1 discussed how atypical chemokine receptors (ACKRs) have emerged as important regulators of chemokines, both in the immune system and beyond. Unlike classical chemokine receptors, ACKRs do not couple to G proteins and thus do not induce cell migration in response to chemokines. Instead, ACKRs regulate chemokine availability in defined tissue microenvironments through ligand sequestration, transport, internalization and delivery for degradation. This year marks the tenth anniversary of the systematic classification of ACKRs by the nomenclature committee of the International Union of Basic and Clinical Pharmacology (IUPHAR)2. Until recently, this subfamily comprised four receptors (ACKR1–ACKR4), but as discussed in the Review, additional molecules are being investigated as potential new members of the ACKR family. In October 2024, one of these molecules, GPR182, was officially recognized by the IUPHAR as ACKR5 (ref. 3) (Fig. 1).

Atypical chemokine receptors (ACKRs) are expressed on different types of endothelial or immune cells. ACKR1 and ACKR2 bind a broad spectrum of inflammatory chemokines that they share with CXCR1–CXCR3 and CCR1–CCR5. ACKR3 binds the homeostatic chemokine CXCL12, which it shares with CXCR4, and the inflammatory CXCL11, shared with CXCR3. ACKR4 interacts with a limited number of mainly homeostatic chemokines that it shares with CCR4, CCR6, CCR7 and CCR9. ACKR5 binds a wide range of XC, CC and CXC chemokines shared with CCR1–CCR10, CXCR2–6 and XCR1. ACKR3 and ACKR5 also bind non-chemokine ligands. For CXCL11, it is depicted in a grey box above ACKR2 as it is an antagonist.

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.