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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. SIGNIFICANCE STATEMENT: Delineating the recognized functions of atypical chemokine receptor 3 and CXCR4 in CXCL12 signaling is central to the more detailed understanding of the role of the CXCL12 system in health and disease and will help to guide future research efforts.

Functions of the CXCL12 Receptor ACKR3/CXCR7—What Has Been Perceived and What Has Been Overlooked