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

Martyna Szpakowska; Giulia D'Uonnolo; Rafael Luís; Ana Alonso Bartolomé; Marcus Thelen; Daniel F Legler; Andy Chevigné

doi:10.3389/fimmu.2023.1133394

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

Front Immunol. 2023 Apr 20:14:1133394. doi: 10.3389/fimmu.2023.1133394. eCollection 2023.

Authors

Martyna Szpakowska¹, Giulia D'Uonnolo^{1

2}, Rafael Luís^{1

2

3}, Ana Alonso Bartolomé^{1

2}, Marcus Thelen⁴, Daniel F Legler⁵, Andy Chevigné¹

Affiliations

¹ Immuno-Pharmacology and Interactomics,Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
² Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
³ Tumor Immunotherapy and Microenvironment, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg City, Luxembourg.
⁴ Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.
⁵ Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland.

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.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Chemotaxis
Clinical Relevance*
Ligands
Protein Binding
Signal Transduction*

Substances

Ligands

Grants and funding

This study was supported by the Luxembourg Institute of Health (LIH), Luxembourg National Research Fund (INTER/FNRS grants 20/15084569 and AFR HOPE-IOID), F.R.S.-FNRS-Télévie (grants 7.4593.19, 7.4529.19, 7.8504.20, 7.4502.21 and 7.8508.22) and the Swiss National Science Foundation (Sinergia CRSII3_160719 (DL and MT)). RL and AAB are the Luxembourg National Research Fund PhD fellows (PRIDE-14254520 “I2TRON” and PRIDE-16749720 “NextImmune2”). GD’U is a F.R.S.-FNRS-Télévie fellow (grant 7.4547.19). AC and MS are part of the Marie Skłodowska-Curie Innovative Training Network ONCORNET2.0 “ONCOgenic Receptor Network of Excellence and Training” (MSCA-ITN-2020-ETN).