Polymorphonuclear neutrophils (PMN) are the most abundant white blood cells in the peripheral blood of humans, and many (though not all) mammals. On average, of the 4500 to 9000 white blood cells found in healthy human adults, 50 to 70 % are PMN. PMN are large cells (average diameter 12-15 µm) with a prominent, loboid nucleus.PMN are produced in the bone marrow, and share common precursor cells with basophils, eosinophils, and monocytes. The circulating PMN pool is constantly renewed; approximately 10 11 cells are produced daily
Role of PMN in the host defence: Traditionally, PMN are associated with the host defence, and often are referred to as the “first line defence”, particularly against bacterial infections. The bactericidal activity is the result of a complex sequence of events briefly outlined here [for extensive reviews see Segal 2005; Underhill and Ozinsky 2002]
Leukocytosis: In response to infection, PMN are released from the bone marrow into the peripheral blood, apparent as leukocytosis, which is also a reliable diagnostic marker for infection, but also for other inflammatory processes, occurring in the absence of an infection. Prolonged infection prompts an increased rate of cell maturation, but also the release of immature cells, apparent in the circulation as cells with a rod-like nucleus.
Diapedesis and chemotaxis: To reach the infected site, PMN actively emigrate from the blood vessel. Following a well-organised hierarchical interaction with endothelial cell surface molecules, PMN adhere to the vessel walls, and eventually squeeze through gaps in between the endothelial cells in process called “diapedesis”. Then PMN migrate actively to the infected site, attracted by so-called “chemokines”, that are produced by the infected tissue and are emitted from there. The PMN recognise the direction by sensing the gradient of those chemokines. Important chemokines for PMN are interleukin 8, the complement split product C5a, bacteria-derived f-methylated peptides (e.g. f-Met-Leu-Phe ), or leukotriene B4, which interact with specific surface receptors
Phagocytosis and bactericidal killing: After having reached the infected site, bacteria, but also other particles, are rapidly taken up by a process known as “phagocytosis”. Phagocytosis requires docking of the bacteria to the PMN, the formation of pseudopods that encloses the bacteria and the fusion of this newly generated “phagosome” with intracellular vesicles (“lysosomes”) that contain bactericidal and proteolytic entities – among others. The main killing mechanism, however, is the generation of reactive oxygen species by a stepwise reduction of oxygen (“oxidative burst”). Phagocytosis and the initiation of the oxidative burst require signalling to the cells. Receptors for characteristic, though not specific bacterial surface molecules (pathogen associated molecular patterns) such as lipopolysaccharides, lipoteichoic acid or proteoglycans have been described on PMN, as have receptors binding to complex carbohydrates. Efficient phagocytosis, however, requires the coating of bacteria with specific antibodies and with complement, which in turn are recognised by receptors binding to the constant part of the attached antibody (hence termed Fc-receptors), or by receptors binding the activated and/or partially degraded form of complement C3 (complement receptors, CR). PMN express constitutively the two Fc-receptors, CD16 and CD32. Upon activation, they transfer a high affinity Fc-receptor, CD64, to the cell surface. Of the four complement receptors, only CR2 (CD21), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) are expressed constitutively, while CR1 (CD35) appears only after activation. Following phagocytosis, PMN undergo apoptosis. The dying cells are cleared by macrophages. This clearance safeguards against the spilling of the cytotoxic content of the PMN, and is thought to limit the action of the PMN in time-and spatial manner, thus minimizing damage to the surrounding tissue [Serhan and Savill, 2005]. Of note, phagocytosis and intracellular killing are not the only means of bactericidal activity: release of bactericidal/antimicrobial and cytotoxic substances is another option [Levy 2000], as is probably the extrusion of DNA and the formation of so-called “neutrophil-extracellular traps
.
