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Published in final edited form as: Free Radic Biol Med. 2012 May 15;53(3):508–520. doi: 10.1016/j.freeradbiomed.2012.05.008

Fig. 1 — Four models of bactericidal action in neutrophils. Panel a: MPO-dependent oxidative killing. Granule-derived MPO catalyzes formation of HOCl from endogenous chloride and NOX-2-derived superoxide or hydrogen peroxide. HOCl and/or secondary chloramines formed by reaction with endogenous amines inactivate plasma membrane-localized proteins involved with energy transduction and biosynthesis (represented here as the F₀F₁-ATP synthase and a generic proton-symporting metabolite transport protein). Additional reactions of HOCl may involve formation of nitryl chloride (NO₂Cl) if sufficient nitrite ion is present in the phagosomal fluid, and generation of hydroxyl and carbonate radicals following one-electron reduction by superoxide. Panel b: MPO-independent oxidative killing. Superoxide ion perfuses the bacterial membrane to react with iron-sulfur clusters in cytosolic dehydratases, releasing ferrous ion, which relocates to vulnerable target sites (here shown as genomic DNA). Subsequent site-specific oxidation by H₂O₂ in Fenton reactions leads to irreversible loss of function (here double-stranded cleavage of the DNA). (After Imlay and coworkers [53].) Additional (but presently controversial) pathways may involve singlet oxygen-initiated formation of hydrogen sesquioxide or ozone in antibody- or amino acid-catalyzed reactions. Panel c: Nonoxidative killing. Granule-derived cationic antimicrobial peptides (CAMP) aggregate in the bacterial plasma membranes to form membrane-spanning pores that dissipate ion gradients essential to homeostasis and energy transduction. In Gram-negative bacteria, granule-derived bactericidal permeability-increasing protein (BPI) binds to lipopolysaccharide (LPS), initiating a set of transformations that promote phospholipase (PLase) activation and access to and degradation of the bacterial membranes by these and other lytic proteins, including serum-derived complement (C₇-C₉) and group IIA-phospholipase A₂ (PLA₂). The latter gain access to the phagosome by binding to extracellular bacteria prior to phagocytosis. PG = peptidoglycan. (After Elsbach and coworkers [23,155].) Panel d: Redox-driven nonoxidative killing. Electrogenic NOX-2 respiration acts to polarize the phagosomal membrane, driving influx of electrolyte cations (here, K⁺). Hydrogen peroxide, formed as the respiratory end-product, is destroyed in catalatic reactions (here via MPO catalysis). The increased ionic strength causes release of granule-derived cationic seprocidins (e.g., cathepsin G, elastase) from anionic biopolymers, which then attack the bacterium. (After Segal and coworkers [41].)

Fig. 1 — Four models of bactericidal action in neutrophils. Panel a: MPO-dependent oxidative killing. Granule-derived MPO catalyzes formation of HOCl from endogenous chloride and NOX-2-derived superoxide or hydrogen peroxide. HOCl and/or secondary chloramines formed by reaction with endogenous amines inactivate plasma membrane-localized proteins involved with energy transduction and biosynthesis (represented here as the F₀F₁-ATP synthase and a generic proton-symporting metabolite transport protein). Additional reactions of HOCl may involve formation of nitryl chloride (NO₂Cl) if sufficient nitrite ion is present in the phagosomal fluid, and generation of hydroxyl and carbonate radicals following one-electron reduction by superoxide. Panel b: MPO-independent oxidative killing. Superoxide ion perfuses the bacterial membrane to react with iron-sulfur clusters in cytosolic dehydratases, releasing ferrous ion, which relocates to vulnerable target sites (here shown as genomic DNA). Subsequent site-specific oxidation by H₂O₂ in Fenton reactions leads to irreversible loss of function (here double-stranded cleavage of the DNA). (After Imlay and coworkers [53].) Additional (but presently controversial) pathways may involve singlet oxygen-initiated formation of hydrogen sesquioxide or ozone in antibody- or amino acid-catalyzed reactions. Panel c: Nonoxidative killing. Granule-derived cationic antimicrobial peptides (CAMP) aggregate in the bacterial plasma membranes to form membrane-spanning pores that dissipate ion gradients essential to homeostasis and energy transduction. In Gram-negative bacteria, granule-derived bactericidal permeability-increasing protein (BPI) binds to lipopolysaccharide (LPS), initiating a set of transformations that promote phospholipase (PLase) activation and access to and degradation of the bacterial membranes by these and other lytic proteins, including serum-derived complement (C₇-C₉) and group IIA-phospholipase A₂ (PLA₂). The latter gain access to the phagosome by binding to extracellular bacteria prior to phagocytosis. PG = peptidoglycan. (After Elsbach and coworkers [23,155].) Panel d: Redox-driven nonoxidative killing. Electrogenic NOX-2 respiration acts to polarize the phagosomal membrane, driving influx of electrolyte cations (here, K⁺). Hydrogen peroxide, formed as the respiratory end-product, is destroyed in catalatic reactions (here via MPO catalysis). The increased ionic strength causes release of granule-derived cationic seprocidins (e.g., cathepsin G, elastase) from anionic biopolymers, which then attack the bacterium. (After Segal and coworkers [41].)