Abstract :
[en] Chemokines and their receptors play a large role in the development and homeostasis of the immune system, as well as its timely recruitment upon tissue injury or inflammation. They are also key mediators in pathological conditions, including cancer and the drive of metastases. This thesis explores the multifaceted roles of the atypical chemokine receptor 3 (ACKR3) which does not signal through the G-protein pathways described for classical chemokine receptors but instead acts as a scavenger for its ligands, directing cell migration along chemokine gradients. More recently, it was shown to bind ligands outside of its described family, namely endogenous opioid peptides, making it the first dual opioid and chemokine receptor. This discovery opens up a novel approach to indirectly target the opioid system, with the potential to mitigate the side effects associated with direct targeting, which, although efficacious, poses serious challenges.
Hence, one of the aims of this thesis was to deepen our understanding of the interplay between ACKR3 and the opioid system. We also delved into the complex biology of ACKR3 and shed light on a novel aspect of its trafficking, namely its release in extracellular vesicles. This is one of several routes cells use to communicate and the discovery of ACKR3 in such vesicles, as well as the mechanisms behind its targeted release, may provide more clarity on the multiple roles this receptor endorses. Finally, this thesis also provided the opportunity to run an in-depth analysis of GPR182, a recently deorphanised G protein-coupled receptor which is also phylogenetically closest to ACKR3, exploring its ligand interactome.
Overall, this interdisciplinary investigation aims to bridge the knowledge gap surrounding ACKR3, providing insights into its role in the opioid system as well as a look into its complex extracellular trafficking profile. The inclusion of GPR182 aims at further enriching our understanding of chemokine receptor function and offering potential targets for therapeutic modulation.
