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How neutrophils kill microbes - PubMed

Review

How neutrophils kill microbes

Anthony W Segal. Annu Rev Immunol. 2005.

Abstract

Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing, and digesting bacteria and fungi. Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species generated by the NADPH oxidase, and by oxidized halides produced by myeloperoxidase. We now know this is incorrect. The oxidase pumps electrons into the phagocytic vacuole, thereby inducing a charge across the membrane that must be compensated. The movement of compensating ions produces conditions in the vacuole conducive to microbial killing and digestion by enzymes released into the vacuole from the cytoplasmic granules.

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Figures

Figure 1
Figure 1

Transmission electron micrograph of a human neutrophil. Inset is an image taken from a neutrophil 20 s after the phagocytosis of latex particles opsonized with IgG (V, vacuole). The section was stained for myeloperoxidase (MPO) to reveal the electron-dense product in the azurophil granules, some of which can be seen degranulating into the phagocytic vacuole (arrows). Bar = 1 μm. (Figure from .)

Figure 2
Figure 2

Schematic representation of the NADPH oxidase. Flavocytochrome b558 is a heterodimer of gp91phox, which contains the haem- and flavin-binding sites, and p22phox. Electron transport is activated by phosphorylation and translocation to the vacuolar membrane of p47phox and p67phox. p21rac, in the GTP-bound form, is also required (12).

Figure 3
Figure 3

The neutral proteases elastase and cathepsin G as well as K+ flux are required for microbial killing and digestion by neutrophils. Cathepsin G, neutrophil elastase (NE), and p47phox (CGD) knockout mice are susceptible to S. aureus (a) and C. albicans (b) in vivo, and their neutrophils kill these organisms poorly in the test tube (c) and (d) (adapted from ​6). Inhibition of the BKCa K+ channel with specific inhibitors paxilline (PAX) and iberiotoxin (IBTX) prevents killing of S. aureus (e), S. marscescens (f ), and C. albicans (g) by neutrophils, whereas the opener NS1619 and nonspecific inhibitor 4-aminopyridine were without effect. The BKCa K+ channel blockers also inhibited digestion of radiolabeled, killed S. aureus (h) (adapted from ​74). Neither the loss of the proteases nor blockage of the BKCa channel affected phagocytosis, oxidase activity, or iodination.

Figure 4
Figure 4

Activity of the NADPH oxidase depolarizes the membrane. The nature of the compensating charge governs the changes in vacuolar pH and tonicity. Electrons are transported across the vacuolar membrane to form O2−, which dismutates to O22−. O2− and O22− become protonated to form HO2 and H2O2, thereby consuming protons and elevating the pH in the vacuole despite the entry of acidic granule contents. This process can only occur if part of the charge is compensated by ions other than protons, which in part occurs through the passage of K+ ions (6, 74).

Figure 5
Figure 5

Schematic representation of interaction between NADPH oxidase and granule proteases. Electron transport through flavocytochrome b558 consumes protons in the vacuole, elevating pH to a level optimal for neutral proteases, which are also activated by K+ driven into the vacuole to compensate the charge across the membrane. The hypertonic K+ solubilizes the cationic granule proteases and peptides by displacing them from the anionic sulphated proteoglycan granule matrix. The requirement for an alkaline, hypertonic environment restricts the toxicity of these proteins to the vacuolar compartment, thereby limiting damage to normal tissues.

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