title: Crosstalk between CXCR4/stromal derived factor-1 and VLA-4/VCAM-1 pathways regulates neutrophil retention in the bone marrow.
abstract: Neutrophil retention in and release from the bone marrow is a critical process that remains incompletely understood. Previous work has implicated the CXCR4/stromal derived factor-1 (SDF-1) chemokine axis in the marrow retention of neutrophils, yet the adhesion pathways responsible for this retention are unknown. Because alpha(4)beta(1) integrin (VLA-4) and its ligand VCAM-1 play a central role in the interactions of hematopoietic stem cells, lymphocytes, and developing neutrophils in the marrow, we investigated whether this integrin might be involved in marrow neutrophil retention and release. In this study, we show that VLA-4 is expressed on murine marrow neutrophils and decreases with maturation, whereas blockade of this integrin leads to the release of marrow neutrophils. Marrow neutrophils adhere via VLA-4 to VCAM-1, which is expressed on marrow endothelium and stroma, and inhibition of VCAM-1 causes release of marrow neutrophils. Furthermore, SDF-1 (CXCL12) signaling through neutrophil CXCR4 augments VLA-4 adhesion to VCAM-1 in vitro, an effect that is blocked by preincubation with pertussis toxin. In vivo blockade of both CXCR4 and alpha(4) causes synergistic release of marrow neutrophils, showing that cross-talk between CXCR4 and VLA-4 modulates marrow retention of these cells. Taken together, these results indicate that the VLA-4/VCAM adhesion pathway is critical in the retention and maturation-controlled release of neutrophils from the marrow, while providing an important link between the CXCR4/SDF-1 signaling axis and the adhesion events that govern this process.
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Petty
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lenox
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weiss
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Suratt
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D054377:Chemokine CXCL12 / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006706:Homeostasis / Q000276:immunology; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D039041:Integrin alpha4beta1; D008024:Ligands; D019718:Receptors, CXCR4; D019010:Vascular Cell Adhesion Molecule-1