Immunity complexity: neutrophiles use nets to kill (Introduction)

by David Turell , Thursday, October 03, 2019, 16:16 (1660 days ago) @ David Turell

Only discovered in the past few years, these nets contain DNA and other molecules:

https://www.the-scientist.com/features/why-immune-cells-extrude-webs-of-dna-and-protein...

"In the early 2000s, Arturo Zychlinsky at the Max Planck Institute for Infection Biology in Berlin found that mammalian immune cells called neutrophils use an enzyme called neutrophil elastase (NE) to cleave bacterial virulence factors. When Zychlinsky and his colleagues delved deeper into this defense mechanism, they realized that when activated by bacteria, human neutrophils release NE in what, under the microscope, looked like a fibrous structure. This structure turned out to be a meshwork of NE, other proteins, and copious amounts of DNA. In cultured human neutrophils, the webs were able to trap the bacteria that had triggered their formation, thereby limiting infection, so Zychlinsky and colleagues dubbed them neutrophil extracellular traps, or NETs.

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"Today, it is widely accepted that NETs have both a protective and a pathological impact on the host. In 2012, Mariana Kaplan, now of the National Institutes of Health, and the University of Tennessee’s Marko Radic termed NETs a “double-edged sword of immunity” and suggested that healthy organisms must tightly control their release to minimize negative consequences for the host. The details of NET regulation and function are now a very active area of research.

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"That said, most pathways of NET formation do kill the immune cell, typically as a result of the production of reactive oxygen species (ROS). Bacterial or fungal pathogens cause neutrophils to activate kinases that induce assembly of an enzyme complex called nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase then produces large amounts of superoxide—a highly reactive oxygen compound that carries an extra electron—during a process called the neutrophil oxidative burst. ROS resulting from the oxidative burst trigger disintegration of a multiprotein complex to release active NE, a primary component of NETs, into the cytoplasm.

"NE then migrates to the neutrophil’s nucleus, where it cleaves histones and other proteins to decondense the chromatin. Eventually, the chromatin fills up the entire cell until the cell lyses and extrudes the NET into the extracellular space, a process known as NETosis. We recently identified an important role for the pore-forming protein gasdermin D in both the nuclear expansion and the lysis processes, although the mechanisms aren’t yet clear. In the extracellular space, the webs are thought to trap and kill the triggering pathogens.

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"The role of NETs in infections is not limited to trapping microbes, however. The structures contain multiple anti-microbial molecules. Histones, for example, are major components of the chromatin in NETs, and these proteins have important bactericidal and immunostimulatory functions.

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"NETs also contain several alarmins, molecules that activate the immune system and help propagate the inflammatory response. Release of alarmin-containing NETs alerts the rest of the immune system to the presence of microbes or foreign substances.

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"Perhaps the most surprising mechanism of NET formation involves DNA release by living neutrophils, a process termed vital NETosis by Kubes and colleagues. It is unclear which molecules mediate DNA release in this case—or how the release even occurs—but it seems that neutrophils remain viable, phagocytic, and are even able to “push” the NET forward as they migrate. These findings demonstrate that neutrophils do not necessarily die after they form NETs."

Comment: Such a complex system must have been designed, as it involved so many different enzymes and protein molecules