New insights into the atypical chemokine receptor network and functions

Chemokines, or chemotactic cytokines, regulate directed cell migration, proliferation and survival by activating seven-transmembrane domain G protein-coupled receptors. A variety of new chemokines were discovered in the 1990s, and it rapidly became clear that the chemokine network is fairly intricate, with most receptors binding multiple ligands and several chemokines binding more than one receptor. Today, there are about 50 chemokines described binding to over 20 different receptors allowing to spatiotemporally fine-tune a multitude of complex biological mechanisms. Besides classical chemokine receptors, a new family of four atypical chemokine receptors (ACKRs) has emerged as important regulators of chemokine functions. ACKRs bind chemokines without triggering G protein signaling but participate in chemotactic events by internalizing chemokines into degradative compartments or by transporting or presenting them on cell surfaces, hence contributing to chemokine gradient formation and clearance of abundant inflammatory chemokines.
Of particular interest for this thesis was ACKR3, which has crucial implications in cardiac and neuronal development, in the migration and homing of hematopoietic stem and progenitor cells, but also in cancer development. ACKR3 binds two chemokines, CXCL12 and CXCL11, which are shared with classical chemokine receptors CXCR4 and CXCR3, respectively. In a first step, we sought to get new insights into the molecular and structural determinants for ACKR3 activation and ligand binding in order to better understand the biology of the receptor. We could show that ACKR3 is a highly activation-prone receptor and that its binding and activation mode differs from its classical chemokine receptor counterparts with which it shares chemokines.
Next, the second and biggest part of this PhD project dealt with uncovering and characterizing new,
non-classical ligands of ACKR3, since it became increasingly clear in the last years that ACKR3 activity
is not limited to chemokine ligands CXCL12 and CXCL11. We revealed that ACKR3 is a broad-spectrum
scavenger for endogenous opioid peptides, regulating their abundance in the central nervous system.
Furthermore, we describe proadrenomedullin-derived peptides as additional family of endogenous
non-chemokine ligands of ACKR3.
Last, we aimed to identify additional chemokine ligands of the atypical chemokine receptors 2 and 4 in order to further extend the already intertwined chemokine-receptor network. By exposing CCL20 and CCL22 as additional ACKR4 ligands, as well as CXCL10 as the first CXC chemokine ligand of ACKR2, our study demonstrated that chemokine-receptor interactions are yet far from being fully characterized and encourages to undertake additional systemic reassessments of the chemokine (and non-chemokine) ligand-receptor network.