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JCB07 Neutrophil DNA Nets

JCB07 Neutrophil DNA Nets - Published January 8 2007 JCB...

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T H E J O U R N A L O F C E L L B I O L O G Y JCB: ARTICLE © The Rockefeller University Press $15.00 The Journal of Cell Biology, Vol. 176, No. 2, January 15, 2007 231–241 http://www.jcb.org/cgi/doi/10.1083/jcb.200606027 JCB 231 Introduction Neutrophils are one of the rst lines of defense against invading microbes (Kanthack and Hardy, 1895; Nathan, 2006). These cells are terminally differentiated, and they have a short life span and low levels of gene expression. When they reach the circulation, they are already equipped with the proteins required to kill microorganisms (Borregaard and Cowland, 1997). Neutro- phils in circulation are directed by cytokines into infected tissues, where they encounter invading microbes. This encounter leads to the activation of neutrophils and the engulfment of the pathogen into a phagosome. In the phagosome, two events are required for antimicrobial activity. First, the presynthesized subunits of the NADPH oxidase assemble at the phagosomal membrane and transfer electrons to oxygen to form superoxide anions. These dismutate spontaneously or catalytically to di- oxygen and hydrogen peroxide. Collectively, superoxide anions, dioxygen, and hydrogen peroxide are called reactive oxygen species (ROS; Hampton et al., 1998). Second, the granules fuse with the phagosome, discharging antimicrobial peptides and enzymes. In the phagosome, microorganisms are exposed to high concentrations of ROS and antimicrobial peptides. Together, they are responsible for microbial killing (Klebanoff, 1999). Patients with mutations in the NADPH oxidase suffer from chronic granulomatous disease (CGD; Heyworth et al., 2003). CGD patients are severely immunode cient, have recurrent infections, often with opportunistic pathogens, and have poor prognosis. Recently, we described a novel antimicrobial mechanism of neutrophils. Upon activation, neutrophils release extra cellular traps (neutrophil extracellular traps [NETs]; Brinkmann et al., 2004). NETs are composed of chromatin decorated with granular proteins. These structures bind Gram-positive and -negative bacteria, as well as fungi (Urban et al., 2006). NETs provide a high local concentration of antimicrobial molecules that kill microbes effectively. NETs are abundant at in amma- tory sites, as shown for human appendicitis and an experimental model of shigellosis. Recently, NETs were shown to be relevant in vivo in human preeclampsia (Gupta et al., 2005) and strepto- coccal infections (Molloy, 2006), causing necrotizing fasciitis (Buchanan et al., 2006) and pneumococcal pneumonia (Beiter et al., 2006). The release of intact chromatin decorated with cytoplasmic proteins into the extracellular space is unprecedented. We describe that activated neutrophils initiate a process where rst the classical lobulated nuclear morphology and the distinction between eu- and heterochromatin are lost. Later, all the internal membranes disappear, allowing NET components to mix. Finally, NETs emerge from the cell as the cytoplasmic membrane is Novel cell death program leads to neutrophil extracellular traps Tobias A. Fuchs, 1,5 Ulrike Abed, 1,2 Christian Goosmann, 1,2 Robert Hurwitz, 3
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