Research ArticleCell death

The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils

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Science Signaling  04 Sep 2018:
Vol. 11, Issue 546, eaao1716
DOI: 10.1126/scisignal.aao1716

Necroptosis NET infection

Neutrophils are innate immune cells that can excrete chromatin upon activation to form neutrophil extracellular traps (NETs). Important for the control of bacterial infections and associated with autoimmunity, NET formation (NETosis) can cause neutrophil cell death. In contrast to apoptosis, necroptosis is a caspase-independent form of cell death. Using transmission electron microscopy and flow cytometry, D’Cruz et al. found that pharmacologic activation of necroptosis, but not apoptosis, stimulated neutrophil NET formation. Inhibition of RIPK1 kinase activity or loss of the necroptosis effector MLKL prevented NETosis and exacerbated methicillin-resistant Staphylococcus aureus (MRSA) infection in mice. These data identify necroptosis as a critical pathway that stimulates NETosis necessary for host defense.

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