Redox Reactions and Microbial Killing in the Neutrophil Phagosome

SIGNIFICANCE: When neutrophils kill microorganisms, they ingest them into phagosomes and bombard them with a burst of reactive oxygen species. RECENT ADVANCES: This review focuses on what oxidants are produced and how they kill. The neutrophil NADPH oxidase is activated and shuttles electrons from NADPH in the cytoplasm to oxygen in the phagosomal lumen. Superoxide is generated in the narrow space between the ingested organism and the phagosomal membrane and kinetic modeling indicates that it reaches a concentration of around 20 μM. Degranulation leads to a very high protein concentration with up to millimolar myeloperoxidase (MPO). MPO has many substrates, but its main phagosomal reactions should be to dismutate superoxide and, provided adequate chloride, catalyze efficient conversion of hydrogen peroxide to hypochlorous acid (HOCl). Studies with specific probes have shown that HOCl is produced in the phagosome and reacts with ingested bacteria. The amount generated should be high enough to kill. However, much of the HOCl reacts with phagosomal proteins. Generation of chloramines may contribute to killing, but the full consequences of this are not yet clear. CRITICAL ISSUES: Isolated neutrophils kill most of the ingested microorganisms rapidly by an MPO-dependent mechanism that is almost certainly due to HOCl. However, individuals with MPO deficiency rarely have problems with infection. A possible explanation is that HOCl provides a frontline response that kills most of the microorganisms, with survivors killed by nonoxidative processes. The latter may deal adequately with low-level infection but with high exposure, more efficient HOCl-dependent killing is required. FUTURE DIRECTIONS: Better quantification of HOCl and other oxidants in the phagosome should clarify their roles in antimicrobial action.