Inflammablog4

Reduce, Reuse, Recycle - Where the Heck is all that DNA Coming From?

Traditionally, two types of cell death have been characterized. Necrosis, that is thought to be unregulated and passive, occurs when a cell is damaged or harmed. Necrosis may lead to inflammation because of the deleterious effects of spewing intracellular contents. In contrast apoptosis is described as programmed cell death, or ordered cell death. The membrane blebs and the chromatin breaks apart, the cell breaks up, but neatly with the cellular contents being enclosed in membrane bound vesicles called apoptotic bodies. Apoptotic bodies are engulfed and endocytosed by phagocytic cells such as Macs and DCs. Multiple proteins, genes, and pathways have been discovered that are important in apoptosis. Lately, one of the hottest topics in immunology has been autophagy. At first it was seen simply as a means through which the cell could respond to stress, eating itself in lean times. Research has been intense in the past five years, and other purposes for this mechanism have been described such as in the controlled destruction and turnover of aging organelles and damaged proteins (3).

Relatively recently a new programmed death mechanism has been uncovered that is unique to leukocytes. Neutrophils and mast cells have been shown capable of activating ETosis. When executed by a neutrophil, it is refered to as NETosis, or the eventual death of the cell due to the formation of neutrophil extracellular traps. In response to bacteria in their environment, neutrophils are capable of casting net like structures on extracellular bacteria. Great high resolution scanning electron micrographs of the NETs are in (2). They consist of smooth fibers with strung globular domains. The smaller fibers have a diameter of 15-17 nm that can assemble into bundled fibers with a diameter up to 50nm. The globular structures have diameters of up to 25 nm. Fonseca et al. demonstrate that the structures consist of DNA and histones, as well as proteins such as elastase (localized to the globular domains) lactoferrin, and gelatinase. The NETs can kill both gram positive bacteria such as Staphylococcus aureus, and gram negative bacteria such as Salmonella typhimurium and Shigella flexneri. The proteases present in NETs, such as elastase, are also capable of disarming secreted bacterial virulence factors such as IcsA and IpaB. In addition, histones in the NET have strong bactericidal property (2). The NETs also physically trap and sequester bacteria, while keeping proteases released by the neutrophil from spreading through tissue (2). The development of NETs follows the decondensation of chromatin and the disintegration of the nuclear envelope and other intracellular membranes (1). Remijsen et al found that NETosis occurs after the initiation of autophagy and superoxide production.

Part of the important function of powerful phagocytes such as this is to clean up and recycle cell debris. In fact this process in pAPC is one route in which autoimmunity may occur (presentation of self-Ags on Macs or DCs leading to activation of Tcells against self). One of the important functions of apoptosis is also another method in which this cellular debris is controlled and degraded in a “safe” manner.

Though NETs would presumably be functional in all people (to achieve optimal immune function) perhaps it goes awry in some. With the uncontrolled dissemination of DNA and histones into tissue, could ETosis be a mechanism through which autoimmunity is initiated. Self DNA appears to be a target of autoimmunity, as SLE patients produce anti-DNA.

(1) Neutrophil extracellular trap cell death requires both autophagy and superoxide generation.

Remijsen Q, Berghe TV, Wirawan E, Asselbergh B, Parthoens E, De Rycke R, Noppen S, Delforge M, Willems J, Vandenabeele P.

Cell Res. 2010 Nov 9. [Epub ahead of print]

(2) Neutrophil Extracellular Traps Kill Bacteria.

Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A.

Science. 2004 Mar 5; 303(5663):1532-5.

(3) Regulation of mammalian autophagy in physiology and pathophysiology.

Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR, Rubinsztein DC.

Physiol Rev. 2010 Oct;90(4):1383-435. Review.