Fig. 2.

A schematic diagram provides an overview of the chemokine system’s different cellular/molecular mechanisms in the CNS. a Post-translational modifications exemplified by CX3CL1 transmembrane form cleavage by ADAM10 and ADAM17 proteases into its soluble variant. b The chemokine family redundancy is exemplified by ACKR3. It belongs to the atypical family since it was regarded as unable to induce G-coupled signaling. It binds two chemokines, CXCL11 and CXCL12. Besides the ACKR3 receptor, these two chemokines activate other chemokine receptors, namely CXCR3 and CXCR4, respectively. c Most chemokine receptors can form homo- and hetero-dimers. It is exemplified by the well-known CXCR4–ACKR3 complex. CXCR4 receptor is a ‘classical’ chemokine receptor, which activates G_αq/i signaling pathways, including PKC or (ERK) ½. As an atypical receptor, ACKR3 alone activates β-arrestin-mediated pathways, leading to receptor internalization or scavenging. However, after heterodimerization with CXCR4, it can modify ligand binding properties and receptor signaling as well as intracellular trafficking. d Chemokine ligand bias occurs when specific chemokines could preferentially activate different intracellular pathways, either G-protein or β-arrestin, although binding to the same receptor. It can be due to a specific ligand or receptor, as exemplified here, due to a specific cell. As suggested recently [27], when ACKR3 is activated on neurons, it signals through β-arrestin-mediated pathways, but when it is activated on astrocytes, it recruits β-arrestin-mediated pathways