New pairings and deorphanization among the atypical chemokine receptor family - physiological and clinical relevance

Abstract

Atypical chemokine receptors (ACKRs) form a small subfamily of receptors (ACKR1-4) unable to trigger G protein-dependent signaling in response to their ligands. They do, however, play a crucial regulatory role in chemokine biology by capturing, scavenging or transporting chemokines, thereby regulating their availability and signaling through classical chemokine receptors. ACKRs add thus another layer of complexity to the intricate chemokine-receptor interaction network. Recently, targeted approaches and screening programs aiming at reassessing chemokine activity towards ACKRs identified several new pairings such as the dimeric CXCL12 with ACKR1, CXCL2, CXCL10 and CCL26 with ACKR2, the viral broad-spectrum chemokine vCCL2/vMIP-II, a range of opioid peptides and PAMP-12 with ACKR3 as well as CCL20 and CCL22 with ACKR4. Moreover, GPR182 (ACKR5) has been lately proposed as a new promiscuous atypical chemokine receptor with scavenging activity notably towards CXCL9, CXCL10, CXCL12 and CXCL13. Altogether, these findings reveal new degrees of complexity of the chemokine network and expand the panel of ACKR ligands and regulatory functions. In this minireview, we present and discuss these new pairings, their physiological and clinical relevance as well as the opportunities they open for targeting ACKRs in innovative therapeutic strategies.

Keywords: ACKR1; ACKR2; ACKR3; ACKR4; ACKR5; CXCR7; D6; GPR182.

Figure 1

ACKR expression, ligand selectivity and crosstalk with classical chemokine receptors. Atypical chemokine receptors are expressed on different types of endothelial or immune cells. ACKR1 and ACKR2 bind a broad spectrum of inflammatory chemokines that they share with CXCR1–3 and CCR1–5. ACKR3 binds the homeostatic chemokine CXCL12, which it shares with CXCR4, and the inflammatory CXCL11, shared with CXCR3. ACKR3 also binds MIF and small non-chemokine peptides such as the proadrenomedullin-derived peptides, ADM and PAMP, as well as several opioid peptides. ACKR4 interacts with a limited number of mainly homeostatic chemokines that it shares with CCR4, CCR7 and CCR9. ACKR5 binds a wide range of both CC and CXC chemokines shared with CCR1, CCR3, CCR5–7 and CXCR3–5 and is still awaiting official IUPHAR recognition as an atypical chemokine receptor (dashed rectangle). Newly identified pairings are indicated in bold. CXCL12–LD: CXCL12 locked dimer.

Figure 2

Overview of the chemokine interaction network with classical and atypical receptors. The interactions between different chemokines and their signaling and regulatory receptors are highly promiscuous. Most chemokines can bind several receptors and the majority of the receptors have multiple ligands. Receptors and chemokines are represented as spheres, while non-chemokine ligands are represented as rounded rectangles. There are 45 chemokines, 19 classical chemokine receptors (light grey) and 5 atypical chemokine receptors: ACKR1 (light blue), ACKR2 (dark blue), ACKR3 (yellow), ACKR4 (red) and the newly proposed ACKR5/GPR182 (light grey). Colored chemokines and non-chemokine ligands represent recently identified pairings, dashed lines indicate proposed ligands and double lines designate the binding of the dimeric ligand to the receptor. Created with BioRender.com.