Neutrophil Extracellular Traps (NETs) -- from infection to autoimmunity

Symposium 5: Caught in a Trap: Neutrophil Extracellular Traps, Reactive Oxygen Species and Inflammation Symp. 5.1

molecular mechanisms of DNA release and its cellular consequences. Keywords: NET, neutrophil, mitochondrial DNA, mitochondria doi:10.1016/j.freeradbiomed.2012.08.096

Neutrophil Extracellular Traps (NETs) – from infection to autoimmunity

Symp. 5.3

A. Zychlinsky* Max Planck Institute for Infection Biology, Germany Neutrophils are one of the first lines of defence of the immune system against microbes. These cells kill microorganisms effectively by phagocytosis and by the formation of extracellular structures, called Neutrophil Extracellular Traps (NETs). NETs are made of chromatin and specific neutrophil proteins and are released after a unique cell death program that requires the production of radical oxygen species (ROS) and the relocation of neutrophil elastase to the nucleus. NETs help limit and control infection and also can activate the acquired immune system. Thus, formation of NETs appears to be necessary for an efficient clearing of microbes but can also initiate and exacerbate autoimmune responses. Keywords: neutrophil, neutrophil extracellular traps, radical oxygen species, infection doi:10.1016/j.freeradbiomed.2012.08.095 Symp. 5.2

Neutrophil Extracellular Trap (NET) formation in the absence of cell death S. Yousefi*, E. Kozlowski, I. Schmid, H-U. Simon University of Bern, Switzerland Besides intracellular killing, neutrophils are able to exert antibacterial activities in the extracellular space by forming so-called neutrophil extracellular traps (NETs). NETs consist of DNA and granule proteins able to bind bacteria and possibly other pathogens. Using time-lapse video microscopy, we demonstrate that NETs can be generated following short-term activation of neutrophils via Toll-like or complement receptors. Cytokine priming but not cell death is required for DNA and granule protein release. Interestingly, the DNA within NETs is of mitochondrial and not nuclear origin. For mitochondrial DNA release, the production of reactive oxygen production is required. Taken together, we report that NET formation represents a functional response following neutrophil activation in the absence of cell death. Further work is required to elucidate the

A novel rapid Neutrophil Extracellular Trap (NET) release mechanism without neutrophil death P. Kubes* University of Calgary, Canada Neutrophils are the primary effector cells in innate immunity. Their role is to kill bacteria via the production of oxidants and proteases. In 2004 Zychlinsky et al uncovered a novel killing mechanism which is the release of chromatin covered with proteases that trap and kill bacteria called Neutrophil Extracellular Traps (NETs). The latter is thought to occur at about 2-4 hours and includes oxidants and lysis of the neutrophil. Under certain conditions NETs can be observed as early as the first 30 minutes of stimulation with pathogens like S. aureus. The NET release is oxidant-independent, occurs via vesicular release and not lysis and despite loss of all nuclear material, the neutrophils remain functional, crawl and phagocytose trapped bacteria. Another way to stimulate this early NET formation is in the blood stream via activated platelets. The platelets bind adherent neutrophils in places like liver sinusoids and increase the ability of the host to trap 4 times more circulating bacteria as a mouse that depends exclusively on macrophage (Kupffer cells) in sinusoids in the absence of NETs. Keywords: Innate Immunity, NETs, S. aureus, Kupffer cells doi:10.1016/j.freeradbiomed.2012.08.097 Symp. 5.4

Neutrophil extracellular traps in the pathogenesis of autoimmune disease D. Scheel-Toellner, University of Birmingham, UK Upon activation, in an active process known as netosis, neutrophils can release their chromatin into the extracellular space. The resulting meshwork of DNA is

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