CXCL14 is a natural inhibitor of the CXCL12–CXCR4 signaling axis

• CXCL14 binds to CXCR4 with high affinity.
• CXCR4 is a major binding component of the CXCL14 receptor.
• CXCL14 inhibits the CXCL12-mediated chemotaxis of immune cells.

Activation of the CXCL12–CXCR4 pathway is crucial for the migration of hematopoietic stem cells, various immune cells, and malignant tumor cells. Here, we show that another CXC chemokine, CXCL14, specifically binds to CXCR4 with high affinity and inhibits the CXCL12-mediated chemotaxis of human leukemia-derived cell lines and CD34+ hematopoietic progenitor cells. Thus, CXCL14 functions as a natural inhibitor of CXCL12. Our observations suggest that CXCL14 represents, along with CXCR7, molecules that co-evolved with the CXCL12–CXCR4 axis to modulate important physiological processes in development, stem cell maintenance, and immune responses.Structured summary of protein interactionsCXCR4physically interacts with CXCL14anti bait coimmunoprecipitation by (View interaction).