Neutrophil extracellular traps (NETs) are extracellular fibrillar networks that concentrate anti-microbial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils. They are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators (e.g., chemokines, cytokines, and complement proteins). The extracellular traps consist of a viscous meshwork of nuclear chromatin that binds and concentrates granule proteins such as anti-microbial peptides and enzymes (
Fig. 3.8 ). NETs provide an additional mechanism of killing microbes that does not involve phagocytosis. In the process of NET formation, the nuclei of the neutrophils are lost, leading to the death of the cells, sometimes called NETosis, representing a distinctive form of cell death affecting neutrophils. NETs also have been detected in the blood during sepsis. The nuclear chromatin in the NETs, which includes histones and associated DNA, may be a source of nuclear antigens in systemic autoimmune diseases, particularly lupus, in which individuals react against their own DNA and nucleoproteins (Chapter 5).
Leukocytes are important mediators of injury to normal cells and tissues under several circumstances:
As part of a normal defense reaction against infectious microbes, when tissues at or near the site of infection suffer collateral damage. In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases such as hepatitis, the prolonged host response contributes more to the pathology than does the microbe itself.
When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases.
When the host “hyper-reacts” against usually harmless environmental substances, as in allergic diseases, including asthma, and some drug reactions.
Leukocytes damage tissues by releasing injurious molecules. The potentially toxic contents of granules are released by leukocytes into the extracellular milieu by several mechanisms. Controlled secretion of granule contents following degranulation is a normal response of activated leukocytes. If phagocytes encounter materials that cannot be easily ingested, such as immune complexes deposited on immovable flat surfaces (e.g., glomerular basement membrane), the inability of the leukocytes to surround and ingest these substances (“frustrated phagocytosis”) triggers strong activation and also the release of large amounts of granule enzymes into the extracellular environment. Some phagocytosed substances, such as urate and silica crystals, may damage the membrane of the phagolysosome and also lead to the release of damaging contents.
Fig. 3.8 Neutrophil extracellular traps (NETs). (A) Healthy neutrophils with nuclei stained red and cytoplasm green. (B) Release of nuclear material from neutrophils (note that two have lost their nuclei), forming extracellular traps. (C) An electron micrograph of bacteria (staphylococci) trapped in NETs. (From Brinkmann V, Zychlinsky A: Beneficial suicide: why neutrophils die to make NETs, Nat Rev Microbiol 5:577, 2007, with permission.) http://ebooksmedicine.net
Other Functional Responses of Activated Leukocytes
In addition to eliminating microbes and dead cells, activated leukocytes play several other roles in host defense. Importantly, these cells, especially macrophages, produce cytokines that can either amplify or limit inflammatory reactions, growth factors that stimulate the proliferation of endothelial cells and fibroblasts and the synthesis of collagen, and enzymes that remodel connective tissues. Because of these activities, macrophages also have centrial roles in orchestrating chronic inflammation and tissue repair, after the inflammation has subsided. These functions of macrophages are discussed later in the chapter.