Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis.
The bone marrow is the primary site for neutrophil production and release into the circulation. Because the CXC chemokine receptor-4/stromal derived factor-1 (CXCR4/SDF-1) axis plays a central role in the interactions of hematopoietic stem cells, lymphocytes, and developing neutrophils in the marrow, we investigated whether reciprocal CXCR4-dependent mechanisms might be involved in neutrophil release and subsequent return to the marrow following circulation. Neutralizing antibody to CXCR4 reduced marrow retention of infused neutrophils (45.7% +/- 0.5% to 6.9% +/- 0.5%) and was found to mobilize neutrophils from marrow (34.4% +/- 4.4%). Neutrophil CXCR4 expression and SDF-1-induced calcium flux decreased with maturation and activation of the cells, corresponding to the decreased marrow homing associated with these characteristics in vivo. Infusion of the inflammatory mediator and CXCR2 ligand KC led to mobilization of neutrophils from marrow by itself and was augmented 3-fold by low doses of CXCR4-blocking antibody that otherwise had no mobilizing effect. Examination of KC and SDF-1 calcium signaling demonstrated that the effect of KC may, in part, be due to heterologous desensitization to SDF-1. These results suggest that the CXCR4/SDF-1 axis is critical in circulating neutrophil homeostasis and that it may participate in the rapid release of neutrophils from the marrow during inflammation through a novel interaction with inflammatory CXC chemokines.
Suratt
Benjamin T
BT
University of Vermont College of Medicine, 149 Beaumont Ave, Burlington, VT 05405, USA. benjamin.suratt@uvm.edu
Petty
Joseph M
JM
Young
Scott K
SK
Malcolm
Kenneth C
KC
Lieber
Jonathan G
JG
Nick
Jerry A
JA
Gonzalo
Jose-Angel
JA
Henson
Peter M
PM
Worthen
G Scott
GS
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism
D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D008024:Ligands; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; C074302:keratinocyte-derived chemokines