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 α4β1 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 α4 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.

Bone Marrow Endothelial Cells Induce Immature and Mature B Cell Egress in Response to Erythropoietin

“…Erythropoietin specifically released immature and mature B cells and T cells from the bone marrow within 24 h, but not other developing B cells (pre-pro, pro, and pre B cells), neutrophils, and HSCs, which also require VCAM1 and CXCL12 for their retention in the bone marrow (Lapidot and Petit, 2002;Ma et al, 1999;Nagasawa, 2006;Petty et al, 2009;Suratt et al, 2004). This specificity implies that these cells, which are not released by erythropoietin from the bone marrow, mainly retain to other bone marrow stromal cells such as MSCs and not to endothelial cells.…”

Neutrophils in cancer: neutral no more

“…Several adhesion molecules, such as integrin subunit α4 (ITGA4) and vascular cell adhesion molecule 1 (VCAM1), as well as some proteases are also important in neutrophil retention [39][40][41] . In addition to its positive influence on granulopoiesis, G-CSF is a well-known disruptor of neutrophil retention 42 .…”

“…Mature cells are retained in the bone morrow by an interplay between two C-X-C chemokine receptors, CXCR4 and CXCR2. Constitutive CXCL12 expression by 4 osteoblasts and other bone marrow stromal cells tether CXCR4 + neutrophils in the bone marrow, whereas secretion of CXCL1 and CXCL2 by endothelial cells and megakaryocytes encourage the release of neutrophils into the circulation via CXCR2 signaling [33][34][35][36][37][38] (Figure 1).Several adhesion molecules, such as integrin subunit α4 (ITGA4) and vascular cell adhesion molecule 1 (VCAM1), as well as some proteases are also important in neutrophil retention [39][40][41] . In addition to its positive influence on granulopoiesis, G-CSF is a well-known disruptor of neutrophil retention 42 .…”

Chemokine Regulation of Neutrophil Infiltration of Skin Wounds

“…Although bone marrow neutrophils express both CXCR2 and CXCR4 on their surface, the CXCL12 dominates to retain most neutrophils within bone marrow through augmented binding of a4 integrin very later antigen (VLA-4) on neutrophils to vascular cell adhesion molecule 1 (VCAM-1) on bone marrow endothelial and stromal cells. 38,39 During maturation in bone marrow, the expression of neutrophil CXCR4 and VLA-4 are downregulated, resulting in a switch of signaling dominance from CXCR4 to CXCR2 that promotes the release of -/ -mice (B), the lack of CXCR2-mediated signaling leads to delayed neutrophil and macrophage recruitment into wound tissues, compromised angiogenesis, and significantly delayed reepithelialization. b-arrestin2 (barr2) binds to the G-protein-coupled receptor kinase phosphorylated C-terminus of CXCR2 and functions as a regulator for CXCR2 signaling.…”