Neutrophil kinetics in health and disease

Abstract

Neutrophils play a key role in the elimination of pathogens. They are remarkably short-lived with a circulating half life of 6-8h and hence are produced at a rate of 5x10(10)-10x10(10) cells/day. Tight regulation of these cells is vital because they have significant histotoxic capacity and are widely implicated in tissue injury. This review outlines our current understanding of how neutrophils are released from the bone marrow; in particular, the role of the CXC chemokine receptor 4/stromal-derived factor 1 axis, the relative size and role of the freely circulating and marginated (i.e. slowly transiting) pools within the vascular compartment, and the events that result in the uptake and removal of circulating neutrophils. We also review current understanding of how systemic stress and inflammation affect this finely balanced system.

Figure 1

Factors that affect the size of the marginated and circulating granulocyte pools. G-CSF is the principal regulator of granulopoiesis and affects the commitment of progenitor cells to the myeloid lineage, proliferation of granulocytic precursors, as well as reducing transit time through the granulocyte compartment and stimulating the release of mature cells from the bone marrow. Neutrophil release from the bone marrow into the total blood granulocyte pool reflects loss of interaction between CXCR4 and SDF-1, and between VLA-4 and VCAM-1. Neutrophils within the total blood pool then enter either the marginated or freely circulating granulocyte pool that are of similar size in humans. A number of factors including exercise, drugs and infection affect the relative size of these two pools, as indicated.

Figure 2

Physiological fate of granulocytes within the blood pool. The absence of infection or injury (which results in the targeted migration of neutrophils into the inflamed tissues), neutrophils exit the total blood granulocyte pool and can be found in the liver, spleen and bone marrow in approximately equal proportions. Neutrophil apoptosis within these tissues results in macrophage recognition and ingestion that leads to G-CSF generation, which in turn stimulates granulopoiesis. Neutrophils within inflamed tissue undergo apoptotic or necrotic cell death or are lost to the body following trans-epithelial migration.

Figure 3

Effects of local and systemic inflammation on neutrophil kinetics. Tissue inflammation results in the release of multiple inflammatory mediators and subsequent neutrophil priming. Priming results in a marked change in neutrophil shape and rheology that leads to retention within the capillary microvascular bed of the lung. The liver is thought to play a particularly important role in recognizing and removing damaged neutrophils. Circulating inflammatory markers stimulate granulopoiesis and rapid release of preformed mature neutrophils from the bone marrow.