PAD 4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps

Peripheral blood neutrophils are the first line of defense after bacterial infection (Segal, 2005; Nathan, 2006). Neutrophils can migrate to sites of infection in response to inflammatory signals, where they engulf and kill bacteria by phagocytosis. Recently, a novel mechanism of extracellular bacterial killing mediated by highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs), was identified (Brinkmann et al., 2004). NET formation is induced by PMA, LPS, and bacteria (Brinkmann et al., 2004). NETs trap and kill pathogenic bacteria, such as Shigella flexneri (Brinkmann et al., 2004) and group A Streptococcus pyogenes (GAS; Buchanan et al., 2006). The role of NETs in innate immunity has kindled much attention due to its involvement in human health and diseases and its therapeutic implications (Brinkmann and Zychlinsky, 2007; Nizet, 2007; Wartha and HenriquesNormark, 2008; von Köckritz-Blickwede and Nizet, 2009). For example, impaired NET formation predisposes newborn infants to bacterial infection (Yost et al., 2009). Further, in chronic granulomatous disease patients with impaired nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and reactive oxygen species (ROS) production, neutrophils cannot generate NETs and possess poor antimicrobial activity (Fuchs et al., 2007; Bianchi et al., 2009). Conversely, gene therapy with the NADPH oxidase gene in a chronic granulomatous disease patient to restore both NET formation and antimicrobial functions has provided an effective treatment for this disease (Bianchi et al., 2009). In the eukaryotic nucleus, 147 bp of DNA is wrapped around a core histone octamer, which includes two of each histone H3, H2B, H2A, and H4, to form a nucleosome. Nucleosomes are 11 nm in diameter and are the basic structural units of chromatin (Richmond and Davey, 2003). The association of linker histone H1 with linker DNA further organizes nucleosomes to form higher-order chromatin structures (Brown CORRESPONDENCE Yanming Wang: yuw12@psu.edu