G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling

Cytokine-induced neutrophilmobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophilmobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophilmobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophilresponse to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor(G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophilmobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophilcounts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophilsin the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophilaccumulation, edema, and inflammationin the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophilmobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophilmobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation.