Neutrophils

Neutrophils (PMNs) are short-lived, highly mobile phagocytes that can ingest bacteria or fungi and kill them by a variety of oxidative and nonoxidative mechanisms. The oxidative mechanisms, which are described in a separate entry, are mediated by molecules whose formation requires superoxide or hydrogen peroxide. In human neutrophils, the antimicrobial oxidants are believed to include hvdroxyl radicals, hypochlorous acid and chloramines. In some species, PMNs and macrophages can also form reactive oxides of nitrogen that possess antimicrobial properties. The nonoxidative mechanisms of neutrophils are mediated, in large part, by potent antimicrobial polypeptides, most of which reside within the cell's numerous cytoplasmic granules. Acting conjointly with the neutrophil's oxidants, these endogenous antibiotics may be delivered directly to microbes sequestered within phagocytic vacuoles or they may be secreted outside the neutrophil to inactivate extracellular microbes. Microorganisms isolated within phagocytic vacuoles can also be deprived of nutrients, subjected to harsh and unfavorable ionic-conditions and low pH, and exposed to potentially noxious surfactants, such as lysolipids. Because the principal peptide antibiotics in human azurophil granules typically exist in concentrations of 1-5 |xg per 10* PMNs, fusion of only 1% of these granules to a phagosome 1 |xm in diameter may result in intraphagosomal concentrations as high as 20100 mg ml"1 for each antimicrobial polypeptide. Under such conditions, interactions and reactions may occur that are not readily predictable from information derived from test-tube experiments.

Approximately a third of the 4500 granules in the cytoplasm of a typical mature human PMN contain myeloperoxidase, and are referred to as 'primary' or 'azurophil' granules. These granules contain most of the PMN's nonoxidative antimicrobial effectors, including defensins, cathepsin G, azurocidin and bactericidal/permeability increasing factor (BPI). The neutrophil's peroxidase-negative granule populations contain the majority of its lysozyme (muramidase), as well as other antimicrobial molecules, such as the a-helical peptide known either as 'EAEL-39" or 'hCAP-18' and a 14 kDa secretory phospholipase A2.

Because azurophil granules are lysosome-like, their internal contents probably remain inert as long as the surrounding granule membrane remains intact. Degranulation, the fusion of granules with the peripheral or perivacuolar plasma membrane, can insert granule membrane contents into the cell's or phagosome's membrane and delivers the granule's antimicrobial contents into the extracellular or phagosomal compartments. In contrast to macrophages, the human neutrophil's phagocytic vacuoles are not as strongly acidic. Studies with fluorescent pH probes indicate that newly formed neutrophil phagosomes are neutral to mildly alkaline for 15-45 minutes, with subsequent acidification to approximately pH 6.0. Initial vacuolar alkalinization and the respiratory burst are linked temporally and perhaps mechanistically.

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