Myeloperoxidase in human neutrophil host defence

Abstract

Human neutrophils represent the predominant leucocyte in circulation and the first responder to infection. Concurrent with ingestion of microorganisms, neutrophils activate and assemble the NADPH oxidase at the phagosome, thereby generating superoxide anion and hydrogen peroxide. Concomitantly, granules release their contents into the phagosome, where the antimicrobial proteins and enzymes synergize with oxidants to create an environment toxic to the captured microbe. The most rapid and complete antimicrobial action by human neutrophils against many organisms relies on the combined efforts of the azurophilic granule protein myeloperoxidase and hydrogen peroxide from the NADPH oxidase to oxidize chloride, thereby generating hypochlorous acid and a host of downstream reaction products. Although individual components of the neutrophil antimicrobial response exhibit specific activities in isolation, the situation in the environment of the phagosome is far more complicated, a consequence of multiple and complex interactions among oxidants, proteins and their by-products. In most cases, the cooperative interactions among the phagosomal contents, both from the host and the microbe, culminate in loss of viability of the ingested organism.

Figure. MPO-dependent events in human neutrophil phagosomes

Concomitant with phagocytosis, human neutrophils assemble and activate the NADPH oxidase and recruit granules to fuse with nascent phagosomes. The NADPH oxidase transfers electrons into the phagosome, generating superoxide anion (O₂^·−) and hydrogen peroxide (H₂O₂) from molecular oxygen. The voltage-gated proton channel Hv1 provides the bulk of charge compensation necessitated by electron transfer from cytoplasm, thereby allowing sustained generation of oxidants in close proximity to the ingested microbe. Chloride (Cl⁻) from the neutrophil cytoplasm enters phagosomes predominantly via cystic fibrosis conductance regulator (CFTR), although ClC3 and KCC3 support some Cl⁻ influx. MPO, provided by azurophilic granules, and H₂O₂ react to yield Compound I (Cpd I), which catalyzes the two electron oxidation of Cl⁻ to Cl⁺ to produce hypochlorous acid (HOCl) or bleach. HOCl reacts with peptides and proteins from host and microbe to generate an array of products, including monochloramines (NH₂Cl), protein chloramines (PNHCl), which can then decompose to form aldehydes. Granule proteins, both native and oxidant-modified, HOCl and its derivatives attack microbial targets, with the outcome dependent both on the number and accessibility of vulnerable targets as well on the defensive responses specific to the ingested organism.