Abstract

The CXCL12 system is central to the development of many organs and is further crucially engaged in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders. This disease-associated role presently focuses major interest on the two CXCL12 receptors, CXCR4 and atypical chemokine receptor 3 (ACKR3)/CXCR7, as promising therapeutic targets. Major obstacles in these ongoing efforts are confusing reports on the differential use of either ACKR3/CXCR7 and/or CXCR4 across various cells as well as on the specific function(s) of ACKR3/CXCR7. Although basically no doubts remain that CXCR4 represents a classic chemokine receptor, functions assigned to ACKR3/CXCR7 range from those of a strictly silent scavenger receptor eventually modulating CXCR4 signaling to an active and independent signaling receptor. In this review, we depict a thorough analysis of our present knowledge on different modes of organization and functions of the cellular CXCL12 system. We further highlight the potential role of ACKR3/CXCR7 as a “crosslinker” of different receptor systems. Finally, we discuss mechanisms with the potency to impinge on the cellular organization of the CXCL12 system and hence might represent additional future therapeutic targets.