Regulation of the Production and Activation of Neutrophils at a Glance
- Human bone marrow commits enormous resources to the creation of neutrophils, producing approximately 1011 daily with a circulating half-life of approximately 7.5 hours and tissue survival for 1–2 days.
- Neutrophils are absolutely required for the prevention of infection and are not yet amenable to significant external replacement therapy.
- The neutrophil not only plays a central role in host defense, it can be responsible for significant tissue damage as well.
- The pathophysiology of the neutrophil indicates pathways, which can be exploited to enhance protection from infection. Selective abrogation of those pathways that are injurious in certain settings is also possible.
- Regulation of neutrophil responses in the skin is a major concern.
This section presents an overview of neutrophil biology and function and uses a few well-characterized defects of myeloid function as illustrations.
Similar to other components of the hematopoietic system, the neutrophil is ultimately derived from a pluripotent hematopoietic stem cell. The development of the myeloid stem cell is largely determined by ambient cytokines and reflected in its surface markers, morphology, and functional characteristics. The myeloblast is fully committed to the neutrophil lineage and is the first morphologically distinct cell in neutrophil development. Subsequent stages of neutrophil development occur under the influence of granulocyte colony-stimulating factor (G-CSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF). Four to six days are required for maturation through the mitotic phase to the myelocyte, and 5–7 days more for the myelocyte to develop into a mature neutrophil, including the metamyelocyte and band stages, before emerging as a fully developed neutrophil. Development of neutrophils through the myelocyte stage normally occurs exclusively in the bone marrow, which is composed of approximately 60% developing neutrophils. The mature neutrophil measures 10–12 μm and has a highly condensed, segmented, multilobulated nucleus, usually with three to five lobes. Although 1011 neutrophils are generated daily, this number can rise tenfold in the setting of infection. The calculated circulating granulocyte pool is 0.3 × 109 cells/kg blood and the marginated pool is 0.4 × 109 cells/kg blood, comprising only 3% and 4% of the total granulocyte pool, respectively. The bone marrow releases 1.5 × 109 cells/kg blood/day to this pool but keeps 8.8 × 109 cells/kg blood in the marrow in reserve. An additional reserve of immature and less competent neutrophils, 2.8 × 109 cells/kg blood, is also available.
G-CSF is critically important for neutrophil production.1 Mice deficient in G-CSF show reduced neutrophil numbers and cannot upregulate neutrophil numbers in response to infection. Interestingly, G-CSF production is under the influence of IL-17, a cytokine of importance in regulation of epithelial defenses.
Granule Content and Function
(Table 30-1.) Neutrophils are characterized by cytoplasmic granules and partially ...