Inclusion of ACKR5 in the systematic nomenclature of atypical chemokine receptors

Abstract

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).

Fig. 1: ACKR ligand selectivity, expression, function and cross-talk with classical chemokine receptors.

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.

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