Beneficial suicide: why neutrophils die to make NETs
Volker Brinkmann and Arturo Zychlinsky
granules to produce a phagolysosome, in which the microorganisms are exposed simultaneously to antimicrobial peptides, enzymes and reactive oxygen species (ROS). These components synergize and effectively kill microorganisms. The fusion of the granules with the phagosome prevents theextracellular release of their potentially noxious components. After phagocytosis, many neutrophils undergo apoptosis in a process that requires CD11b/CD18 (Mac1), the production of ROS and activation of caspases7,8. Apoptotic neutrophils are swiftly removed by macrophages, preventing the release of neutrophil proteins that can cause tissue damage9,10. Neutrophils kill microorganisms throughoxygen-independent and oxygen-dependent mechanisms. The oxygen-independent mechanisms include the release of peptides and proteins from the granules, such as bactericidal permeability-increasing proteins (BPI), defensins and cathelicidins11. Although these proteins are structurally and evolutionarily unrelated, they are all highly cationic. The positive charge probably mediates the initial binding tomicroorganisms, as the surfaces of bacteria and fungi are mostly anionic. Once bound, antimicrobial proteins might disrupt the integrity of the bacterial membrane, although the detailed mechanisms involved in toxicity are not yet understood. The oxygen-dependent antimicrobial killing starts with the assembly of the multimeric NADPH oxidase enzyme complex at the phagosomal membrane. This complex oxidizesNADPH, releasing two electrons that are transferred to O2. This results in the formation of superoxide (O2– ), which dismutates — either spontaneously or catalytically (driven by superoxide dismutase (SOD)) — into hydrogen peroxide (H2O2). The H2O2, in turn, is converted to hypochlorite (HOCl) by myeloperoxidase (MPO). These ROS are essential for bacterial killing and are thought to function byoxidizing proteins, nucleic acids and other molecules12. Owing to their short half-life it has been difficult to demonstrate that ROS levels in phagolysosomes reach microbicidal concentrations. Interestingly, however, microorganisms that encode SODs, which
Abstract | Neutrophils are one of the main types of effector cell in the innate immune system and were first shown to effectively killmicroorganisms by phagocytosis more than 100 years ago. Recently, however, it has been found that stimulated neutrophils can also produce extracellular structures called neutrophil extracellular traps (NETs) that capture and kill microorganisms. This Progress article gives an overview of the structure, function and generation of NETs, and their role in infections.
Neutrophils are essential effector cells ofthe innate immune system. They mature in the bone marrow and, when terminally differentiated, they are released into the bloodstream, where they have a half-life of only a few hours. Under normal conditions, neutrophils constitute around 60% of all the white blood cells in humans1. In healthy individuals most neutrophils are destined to be cleared without ever executing their function. Duringinfection, however, neutrophils are one of the first cell types to be recruited to inflammatory sites, where they have a crucial role in the clearance of microorganisms. For an elegant recent review on neutrophils, readers are referred to REF. 2. Neutrophils are also known as polymorphonuclear cells or granulocytes, referring to their morphology and staining characteristics (FIG. 1a). They have aunique polymorphic nucleus that, in humans, is segregated into 3–5 lobules, each with a diameter of approximately 2 µm. It is thought that this arrangement might make the nucleus more pliable and allow neutrophils to pass through gaps in the endothelium. The term granulocyte refers to a second morphological hallmark of neutrophils: these cells have numerous granules in the cytoplasm that are...