STAT3 controls the neutrophil migratory response to CXCR2 ligands by direct activation of G-CSF-induced CXCR2 expression and via modulation of CXCR2 signal transduction.
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 macrophage-inflammatory protein-2 (MIP-2; CXCL2), can induce neutrophil mobilization, but the mechanism(s) they use remain unclear. Signal transducers and activator of transcription 3 (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 STAT3 regulates acute G-CSF-responsive neutrophil mobilization and MIP-2-dependent neutrophil chemotaxis. In this study, we show STAT3 is also necessary for MIP-2-elicited neutrophil mobilization. STAT3 appears to function by controlling extracellular signal-regulated kinase (ERK) activation, which 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 STAT3-dependent changes in bone marrow chemokine expression levels 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.
Nguyen-Jackson
Hoainam
H
Department of Immunology and Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Panopoulos
Athanasia D
AD
Zhang
Huiyuan
H
Li
Haiyan S
HS
Watowich
Stephanie S
SS
D000818:Animals; D002469:Cell Separation; D054426:Chemokine CXCL2 / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D053700:Receptors, Interleukin-8; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D053700:Receptors, Interleukin-8; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor