Neutrophil microbicidal activities; a.) Following phagocytosis of microbes, fusion of neutrophil granules with the phagosome introduces antimicrobial granule contents into the phagosome. Non-azurophilic granules transport the membrane bound components of the NADPH oxidase into the phagosome, where they assemble with cytoplasmic components. The assembled NADPH oxidase transfers an electron from cytosolic NADPH to oxygen, forming O2−. O2− is converted into H2O2, and MPO combines H2O2 with Cl to form HOCl. b.) NETs are large, extracellular webs of microbicidal cytosolic and granule proteins assembled on a scaffold of decondensed chromatin or mitochondrial DNA (not shown). NET formation may be initiated by a variety of pathogenic triggers. In classic NADPH oxidase-dependent NETotic cell death, ROS trigger MPO to activate and translocate of NE from azurophilic granules to the nucleus, where NE disrupts chromatin packaging. MPO also works synergistically with NE in decondensing chromatin. Two nuclear enzymes are important in chromatin decondensation; DEK, a DNA-binding protein, and PAD4, which citrullinates histone arginine residues.
(H2O2: hydrogen peroxide; HOCl: hypochlorous acid; MPO: myeloperoxidase; NADPH: nicotinamide adenine dinucleotide phosphate; NE: neutrophil elastase; NET: neutrophil extracellular trap; O2•−: superoxide; PAD4: protein-arginine deiminase type 4; ROS: reactive oxygen species)