STAT3 Controls the Neutrophil Migratory Response to CXCR2 Ligands by Direct Activation of G-CSF-Responsive CXCR2 Expression and Via Modulation of CXCR2 Signal Transduction .

Abstract 236

Neutrophil mobilization, the release of neutrophils from the bone marrow reserve into circulating blood, is important to increase peripheral neutrophil amounts during bacterial infections. Granulocyte colony-stimulating factor (G-CSF) and chemokines, such as MIP-2 (CXCL2), can induce neutrophil mobilization, but the mechanism(s) they employ remain unclear. The transcription factor STAT3 is the principal intracellular signaling molecule activated upon G-CSF-ligation of its receptor. Using a murine model with conditional STAT3 deletion in bone marrow, we demonstrated previously that acute G-CSF-responsive neutrophil mobilization and MIP-2-dependent neutrophil chemotaxis is mediated by STAT3. In this study, we show that STAT3 is also necessary for MIP-2-elicited neutrophil mobilization. STAT3 appears to function by regulating the amplitude of Raf/MEK/Erk activation by MIP-2, a signaling pathway that is important for MIP-2-mediated chemotaxis. In addition, we demonstrate that G-CSF stimulates the expression of the MIP-2 receptor via STAT3-dependent transcriptional activation of Il8rb. G-CSF treatment also induces changes in bone marrow chemokine expression levels in a STAT3-dependent manner, which may further affect neutrophil retention and release. Taken together, our study demonstrates that STAT3 regulates multiple aspects of chemokine and chemokine receptor expression and function within the bone marrow, indicating a central role in the neutrophil mobilization response.