The immune system depends on chemokines to direct cell migration during immune surveillance and inflammation, as well as to play vital roles in the development, maturation, and homing of lymphocytes and the development of organs. However, an imbalance in the chemokine system can also contribute to various diseases, such as inflammatory conditions and cancer. In all these situations, chemokines interact with seven-transmembrane chemokine-type G protein-coupled receptors (chemokine receptors, CKRs) and glycosaminoglycans (GAGs) to regulate the movement of leukocytes throughout the body, ensuring a functional immune system and an effective response to inflammatory stimuli (Proudfoot, A. E, 2002).
In humans there are approximately 45 chemokines, 19 chemotactic or G-protein coupled chemokine receptors (CKRs) that signal via Gαi and 4 official atypical chemokine receptors (ACKRs) which engage in ligand scavenging and favor β-arrestin biased signaling (Murphy, PM. et al. 2000). Indeed, ACKRs behave as scavenging “decoys” in order to either limit chemokines spatial availability or to remove them from in vivo sites, while maintaining the responsiveness of canonical G protein-coupled CKRs that bind to the same ligand(s) (Nibbs, R. J.; Graham, G. J., 2013).
Although less characterized, canonical CKRs have also been shown to not only directly regulate migration but also play a scavenging role (e.g. CCR2, CXCR2, CXCR3, and CX3CR1) (Cardona, A. E., et al. 2008). CCR2 is an example of a dual-function receptor that directly regulates both cell migration and scavenging (Volpe S. et al., 2012), which molecular signature was recently characterized (Shroka, T. M, et al. 2023). This study revealed that CCR2 scavenging is independent of G proteins, GRKs, arrestins, as well as clathrin, which is a different mechanism from what has been established for other chemokine scavenger receptors that where shown to couple to GRKs, β-arrestins, or both such as CCR1. CCR1 is constitutively phosphorylated, constitutively interacts with β-arrestin2, and constitutively internalizes in a β-arrestin2-dependent manner (Gillilan, C. T., et al., 2013).
Scavenging allows cells to continuously migrate by remaining responsive to chemokines, it dampens the inflammatory response when needed; and it may interfere with other chemokine receptors which share the ligands and ultimately affect cell migration (Cardona, A. E., et al. 2008). Interestingly, in monocytes and dendritic cells exposed to treatments mimicking inflammation, CCR1, CCR2, and CCR5 switch purely to scavenging (D'Amico G. et al. 2000), becoming incapable of promoting cell migration, a phenomenon which is likely to be mediated by changes in the cell motility machinery with receptor-specific switches.
The scavenging function of CKRs should be considered when evaluating the safety and therapeutic efficacy of blocking receptor-ligand binding. For instance, CCR2 inhibition leads to inhibition of scavenging and elevated plasma levels of CCL2 (Aiello, R. J., et al. 2010), which may ultimately compete with receptor antagonists, thereby decreasing the efficacy.
To comprehensively elucidate the role of scavenging in normal physiology and the potential implications of its inhibition, an in-depth understanding of the underlying regulatory mechanisms is needed. Enhancing our knowledge of these regulatory frameworks will provide critical insights into the contribution of scavenging to homeostatic maintenance and the pathological consequences that may arise from its disruption.
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