Neutrophil mobilization and clearance in the bone marrow

Abstract

The bone marrow is the site of neutrophil production, a process that is regulated by the cytokine granulocyte colony-stimulating factor (G-CSF). Mature neutrophils are continually released into the circulation, with an estimated 10(11) neutrophils exiting the bone marrow daily under basal conditions. These leucocytes have a short half-life in the blood of approximately 6.5 hr, and are subsequently destroyed in the spleen, liver and indeed the bone marrow itself. Additionally, mature neutrophils are retained in the bone marrow by the stromal cell-derived factor (SDF-1alpha)/chemokine (C-X-C motif) receptor 4 (CXCR4) chemokine axis and form the bone marrow reserve. Following infection or inflammatory insult, neutrophil release from the bone marrow reserve is substantially elevated and this process is mediated by the co-ordinated actions of cytokines and chemokines. In this review we discuss the factors and molecular mechanisms regulating the neutrophil mobilization and consider the mechanisms and functional significance of neutrophil clearance via the bone marrow.

Figure 1

Neutrophils which are mobilized from the bone marrow must cross the sinusoidal endothelium. (a) Electron micrograph illustrating the transcellular migration of a neutrophil (arrow) through murine bone marrow sinusoidal endothelium (arrowheads) into the lumen following infusion of 0·1 mm of the chemokine (C-X-C motif) receptor 4 (CXCR4) antagonist AMD3100 (Sigma Aldrich, Poole, UK) for 10 min, followed by 20 min with buffer alone, prior to perfusion fixation and preparation for transmission electron microscopy. (b) Migration of a neutrophil across the sinusoidal endothelium following infusion of macrophage inflammatory protein (MIP)-2. Rat femoral bone marrow was infused with MIP-2 (3 nmol/l) for 10 min, followed by 20 min with buffer alone, prior to perfusion fixation and preparation for scanning electron microscopy.

Figure 2

Granulocyte colony-stimulating factor (G-CSF) and ELR (Glu-Leu-Arg motif) + CXC chemokines act in a co-ordinated manner to mobilize and recruit neutrophils to the site of inflammation. G-CSF (blue arrows) and the ELR + CXC chemokines macrophage inflammatory protein (MIP)-2 and KC (green arrows) act to mobilize neutrophils from the bone marrow into the circulation; however, only MIP-2 and KC recruit neutrophils from the blood to the site of inflammation. KC and MIP-2 act via chemokine CXC receptor 2 (CXCR2) on neutrophils, whereas G-CSF down-regulates the expression of CXCR4 on neutrophils, thus reducing retention via the CXCR4/stromal cell-derived factor (SDF-1α) axis and mobilizing neutrophils into the circulation.

Figure 3

Proposed mechanism for neutrophil production and clearance in the bone marrow under homeostatic conditions. Granulocyte colony-stimulating factor (G-CSF) promotes the differentiation of mature neutrophils from myeloid precursors in the bone marrow. Stromal cell-derived factor (SDF-1α) is expressed constitutively in the bone marrow, and mature neutrophils, which express low levels of chemokine (C-X-C motif) receptor 4 (CXCR4), are retained via the CXCR4/SDF-1α axis. In the absence of inflammation, neutrophils become senescent and express high levels of CXCR4, directing them back to the bone marrow. Once in the haematopoietic compartment of the marrow, neutrophils become apoptotic and are engulfed by resident stromal macrophages, which subsequently induces the production of G-CSF by the bone marrow macrophages.