Murine Bone Marrow Stromal Cell Response to Granulocyte Colony-Stimulating Factor

Neutrophil homeostasis is maintained, in part, by the regulated release of neutrophils from the bone marrow. Constitutive expression of the chemokine CXCL12 by bone marrow stromal cells provides a key retention signal for neutrophils in the bone marrow through activation of its receptor CXCR4. Herein, we show that the ELR chemokines CXCL1 and CXCL2 are constitutively expressed by bone marrow endothelial cells and osteoblasts, and CXCL2 expression is induced in endothelial cells during granulocyte colony-stimulating factor (G-CSF)-induced neutrophil mobilization. Neutrophils lacking CXCR2, the receptor for CXCL1 and CXCL2, are preferentially retained in the bone marrow, reproducing a myelokathexis phenotype. Transient disruption of CXCR4 failed to mobilize CXCR2 neutrophils. However, doubly deficient neutrophils (CXCR2-/- CXCR4-/-) displayed constitutive mobilization, showing that CXCR4 plays a dominant role. Collectively, these data suggest that CXCR2 signaling is a second chemokine axis that interacts antagonistically with CXCR4 to regulate neutrophil release from the bone marrow. We used gene expression microarrays to determine the changes in osteoblasts and bone marrow endothelial cells after G-CSF treatment.