Abstract
NETosis is a unique form of neutrophil death that differs from apoptosis and necrosis. However, whether NETosis and apoptosis can occur simultaneously in the same neutrophil is unknown. In this paper, we show that increasing doses of ultraviolet (UV) irradiation increases NETosis, which is confirmed by myeloperoxidase colocalisation to neutrophil extracellular DNA. Increasing UV irradiation increases caspase 3 activation, mitochondrial reactive oxygen species (ROS) generation and p38, but not ERK, phosphorylation. Inhibition of mitochondrial ROS production and p38 activation, but not NADPH oxidase (NOX) activity, suppresses UV-induced NETosis, indicating that UV induces NOX-independent NETosis. Like classical NOX-dependent and -independent NETosis, UV-induced NETosis requires transcriptional firing for chromatin decondensation. Cell death-specific inhibitor studies indicate that UV-mediated NETosis is not apoptosis, necrosis or necroptosis. Collectively, these studies indicate that increasing doses of UV irradiation induce both apoptosis and NETosis simultaneously, but the ultimate outcome is the induction of a novel form of NOX-independent NETosis, or “ApoNETosis”.
Highlights
NETosis is a novel and distinct form of neutrophil death that results in the formation and release of neutrophil extracellular traps (NETs)[1,2,3,4,5,6]
SYTOX Green is a cell-impermeable dye that fluoresces green upon binding to DNA released by neutrophils; the amount of green fluorescence signal of this probe acts as a measure of NETosis
We have identified that UV-induced NETosis is rapid, and follows the kinetics typical for NADPH oxidase (NOX)-independent NETosis
Summary
NETosis is a novel and distinct form of neutrophil death that results in the formation and release of neutrophil extracellular traps (NETs)[1,2,3,4,5,6]. NETs have been reported to originate from neutrophil mitochondria[9]. NETosis may be beneficial during infection-related inflammation[10,11], excess NET formation, during sterile inflammation, can damage tissue and organs[4,12,13,14] and has been implicated in many disease states[15,16,17]. Understanding the molecular mechanisms of various forms of NETosis is important for regulating unwanted NET formation. The molecular mechanism of NETosis, when induced by irradiation, has not been elucidated. Two major types of NETosis have been described: NADPH oxidase (NOX)-dependent NETosis and NOX-independent
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