Regulation of the Production and Activation of Neutrophils



Regulation of the Production and Activation of Neutrophils: Introduction




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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.





Neutrophils





This section presents an overview of neutrophil biology and function and uses a few well-characterized defects of myeloid function as illustrations.






Ontogeny and Development



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.






Biologic Functions



Granule Content and Function



(Table 30-1.) Neutrophils are characterized by cytoplasmic granules and partially condensed nuclei. Granules are first found at the promyelocyte stage.2 Primary (azurophilic) granules are the first to arise, measure approximately 0.8 μm in diameter, and contain numerous antimicrobial products including lysozyme, myeloperoxidase, and defensins.3 Primary granules are only synthesized at the promyelocyte stage. The promyelocyte gives rise to the myelocyte, the last cell of the neutrophil lineage with proliferative potential. Therefore, cytokines or agents that increase total neutrophil production must act at or before the myelocyte stage. The smaller eosinophilic secondary (specific) granules appear during the myelocyte stage. These granules measure about 0.5 μm in diameter and contain lactoferrin, collagenase, gelatinase, vitamin B12-binding protein, and complement receptor 3 (CR3; CD11b/CD18). gp91phox and p22phox comprise the specific granule component cytochrome b558, defects in which cause chronic granulomatous disease (CGD), characterized by infections with particular catalase-producing bacteria. Gelatinase also cleaves and potentiates the activity of the chemokine interleukin-8 (IL-8). Because primary granules are synthesized early and distributed to daughter cells during division, they are eventually outnumbered by about 3:1 by the specific granules, which are produced throughout the myelocyte stage.




Table 30-1 Human Neutrophil Components 



Granules fuse in a sequential fashion with incoming phagocytic vacuoles, such as those containing ingested bacteria. Secondary granules fuse to the phagosome within the first 30 seconds after ingestion and release their enzymes, many of which function best at neutral or alkaline pH. By 3 minutes after ingestion, the primary granules have fused to the phagolysosome leading to rapid lowering of the intravacuolar pH. For objects too large to be ingested, or certain stimuli, degranulation to the cell surface occurs with release of granule contents into the surrounding environment. This can be inferred by detection of lactoferrin levels in blood.



An example of disordered granule biogenesis is Chédiak–Higashi syndrome (CHS), a rare autosomal recessive disorder with abnormal pigmentation due to a generalized abnormality of primary granule and lysosome formation (see Chapter 143).



Neutrophil-Specific Granule Deficiency



Neutrophil-specific granule deficiency is a rare, autosomal recessive condition clinically characterized by a profound susceptibility to bacterial infections. There is a paucity or absence of neutrophil-specific granules, specific granule proteins (e.g., lactoferrin) and their respective messenger RNAs, and very low levels of the primary granule products defensins and their messenger RNAs. Specific granule deficiency is due to loss of the transcriptional factor CCAAT/enhancer binding protein ε (CEBPε), which is essential in normal myeloid development. Acquired abnormalities of neutrophil granules are seen in some myeloid leukemias, in which primary granule contents may be aberrantly accumulated (e.g., Auer rods in acute myelogenous leukemia).






Tissue Trafficking



Chemoattractants and Chemotaxis



Metchnikoff discovered over a century ago that neutrophils move toward very slight gradients of chemical signals, now termed chemoattraction. The “classic” chemoattractants are N-formylmethionyl-leucyl-phenylalanine (fMLF), complement factor 5a (C5a), leukotriene B4, and platelet-activating factor (PAF). More recently, chemokines (chemoattractant cytokines), a class of small (<10 kDa) extremely active chemoattractant proteins have been identified (see Chapter 12).

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Jun 11, 2016 | Posted by in Dermatology | Comments Off on Regulation of the Production and Activation of Neutrophils

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