CXCL12CXCR4

The CXCL12-CXCR4 axis refers to the signaling interaction between the chemokine CXCL12 (stromal cell-derived factor-1, SDF-1) and its receptor CXCR4, a G protein-coupled receptor. CXCL12 is produced by stromal cells and endothelial cells in bone marrow and other tissues, creating gradients that attract CXCR4-expressing cells. CXCR4 is widely expressed on hematopoietic stem and progenitor cells, immune cells, endothelial cells, and many cancer cells. The axis plays a central role in hematopoietic stem cell homing to the bone marrow and in embryonic development of the cardiovascular and nervous systems, as well as in inflammatory responses and tissue repair.

Signaling begins when CXCL12 binds CXCR4, activating Gi/o proteins and downstream pathways including PI3K-Akt and MAPK-ERK, increasing intracellular calcium and promoting cytoskeletal changes that drive chemotaxis, migration, survival, and proliferation. The axis also influences angiogenesis and cell retention within tissues.

Pathological and clinical highlights: the CXCL12-CXCR4 axis supports cancer cell metastasis by guiding tumor cells to CXCL12-rich organs such as bone, liver, and lungs, and it participates in HIV-1 entry via CXCR4 in susceptible cells. Therapeutically, CXCR4 antagonists (for example, plerixafor/AMD3100) are approved to mobilize hematopoietic stem cells for transplantation, and other antagonists are under clinical investigation for cancer and fibrotic diseases. The axis interacts with related receptors such as CXCR7/ACKR3, which can bind CXCL12 and modulate signaling dynamics.