期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 9, 页码 2817-2822出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1414055112
关键词
neutrophils; neutrophil extracellular traps; NETosis; NADPH oxidase; SK channels
资金
- Ontario Graduate Scholarship
- Ontario Student Opportunity Trust Fund (SickKids Restracomp)
- Ontario Student Opportunity Trust Fund (Dr. Goran Enhorning Award in Pulmonary Research)
- Ontario Student Opportunity Trust Fund (Peterborough K.M. Hunter Graduate Studentship)
- University of Toronto Doctoral Thesis Completion Grant
- SickKids Research Institute's Trainee Start Up Fund
- Canadian Institutes of Heath Research [MOP-111012]
- Cystic Fibrosis Canada [2619]
Neutrophils cast neutrophil extracellular traps (NETs) to defend the host against invading pathogens. Although effective against microbial pathogens, a growing body of literature now suggests that NETs have negative impacts on many inflammatory and autoimmune diseases. Identifying mechanisms that regulate the process termed NETosis is important for treating these diseases. Although two major types of NETosis have been described to date, mechanisms regulating these forms of cell death are not clearly established. NADPH oxidase 2 (NOX2) generates large amounts of reactive oxygen species (ROS), which is essential for NOX-dependent NETosis. However, major regulators of NOX-independent NETosis are largely unknown. Here we show that calcium activated NOX-independent NETosis is fast and mediated by a calcium-activated small conductance potassium (SK) channel member SK3 and mitochondrial ROS. Although mitochondrial ROS is needed for NOX-independent NETosis, it is not important for NOX-dependent NETosis. We further demonstrate that the activation of the calcium-activated potassium channel is sufficient to induce NOX-independent NETosis. Unlike NOX-dependent NETosis, NOX-independent NETosis is accompanied by a substantially lower level of activation of ERK and moderate level of activation of Akt, whereas the activation of p38 is similar in both pathways. ERK activation is essential for the NOX-dependent pathway, whereas its activation is not essential for the NOX-independent pathway. Despite the differential activation, both NOX-dependent and -independent NETosis require Akt activity. Collectively, this study highlights key differences in these two major NETosis pathways and provides an insight into previously unknown mechanisms for NOX-independent NETosis.
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