G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells

CXCR4 receptor expression is required for the retention of granulocyte precursors and mature neutrophils within the bone marrow, and disruption of the SDF1/CXCR4 axis in the bone marrow results in the mobilization of myeloid lineage cells to the peripheral circulation. We report that G-CSF down-regulates CXCR4 expression in bone marrow-derived murine and human myeloid lineage cells. When exposed to G-CSF, murine Gr1(+) bone marrow myelold cells display a timedependent reduction of cell-surface CXCR4 and respond poorly to SDF-1 in attachment and migration assays. Bone marrow-derived cells of nonmyeloid lineage display no change in surface CXCR4 expression upon exposure to G-CSF. Compared with controls, mice treated with G-CSF for mobilization of hematopoietic progenitor cells display reduced levels. of CXCR4 selectively in bone marrow Gri(+) myelold cells. Since bone marrow myeloid cells express G-CSF receptors and G-CSF rapidly reduces CXCR4 expression in purified Gr1(+) cells populations, these results provide evidence that GCSF acts directly on myeloid lineage cells to reduce CXCR4 expression. By downregulating CXCR4 expression in bone marrow myeloid cells and attenuating their responsiveness to SDF-1, G-CSF promotes their mobilization from the bone marrow to the peripheral blood.