The neutrophil nucleus as a signaling hub during chemotaxis and DNA release

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Research in the Parent lab aims at understanding the mechanisms by which cells reach sites of infection and injury. In particular, our work focuses on neutrophils, the most abundant leukocyte in human blood and first line of defense against insult. We found that, in response to primary chemoattractants, neutrophils secrete the secondary chemoattractant leukotriene B4 (LTB4), which dramatically amplifies the recruitment range of neutrophils to sites of infection or injury. LTB4 is synthesized from the cytosolic phospholipase 2 alpha (cPLA2α)-mediated release of arachidonic acid through the action of the cytosolic enzyme 5-lipoxygenase (5-LO), the endoplasmic reticulum/nuclear envelope-resident protein 5-lipoxygenase activating protein (FLAP) and leukotriene A4 hydrolase. Neutrophil activation triggers the packaging of the LTB4 synthesizing machinery within nuclear envelope-derived multivesicular bodies, which release exosomes that secrete LTB4 to recruit distant neutrophils to infected/injured sites. We also found that chemotaxing neutrophils release nuclear DNA in a non-lytic, rapid, and repetitive manner. The packaging of DNA occurs in the lumen of these same nuclear envelope-derived multivesicular bodies. The mechanisms underlying this response as well as its physiological consequence will be presented.