Sepsis is a deadly systemic inflammatory response syndrome caused, most often, by a bacterial infection. This complex syndrome frequently progresses to severe sepsis or septic shock, resulting in high mortality rates in intensive care unit (ICU) worldwide. Neutrophils are the major immune cells involved in sepsis and crucial to patient survival. Through several effector mechanisms such as phagocytosis, reactive oxygen species (ROS) production, nitric oxide (NO) generation and neutrophil extracellular trap (NET) release, these cells kill a range of microbes. NETs are recently uncovered neutrophil effectors, and are composed of DNA, histones and cytotoxic enzymes. To release NETs, activated neutrophils undergo a different form of cell death, called "NETosis". Initially discovered form of NETosis depends on NADPH oxidase (NOX2) of the neutrophils. Recently, it was demonstrated that neutrophils also release NETs, via vesicular trafficking, and remain alive and functional. It was called "vital NETosis", which is independent of NOX2 activation. However, until now, little is known about the molecular mechanisms of various types of NETosis. Palaniyar's group described the importance of AKT activation to inhibit neutrophil apoptosis and to direct cell death to NETosis. Moreover, they verified that NETosis induced by calcium ionophore is fast, NOX2-independent, and is mediated by mitochondrial ROS and a calcium activated small conductance potassium 3 (SK3) channel. In the sepsis context, NETs release is a double-edged sword. Although NETs are crucial for pathogen clearance, they are important contributors to organ damage. Searching for new therapeutic targets to treat organ damage-related NETs in sepsis is crucial. Therefore, our aim is to determine the major mechanisms that induce NETosis in septic neutrophils and identify potential drug targets to treat sepsis.
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