Editors' ChoiceImmunology

Stimulating NETosis instead of mitosis

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Sci. Signal.  05 Dec 2017:
Vol. 10, Issue 508, eaar6334
DOI: 10.1126/scisignal.aar6334

Cell cycle regulators control the production of neutrophil extracellular traps.

When neutrophils encounter pathogens that are too large to phagocytose, the neutrophils undergo a peculiar form of cell death (NETosis) in which they extrude antimicrobial proteins bound to chromatin. These neutrophil extracellular traps (NETs) concentrate and immobilize the same antimicrobial factors that are released when neutrophils degranulate. NETosis is characterized by mitogen-activated protein kinase (MAPK) signaling and breakdown of the nuclear envelope, both of which also occur during mitosis, as well as the production of reactive oxygen species (ROS) that cause the protease elastase to translocate to the nucleus, where it cleaves histones to decondense chromatin. Amulic et al. found that plant-derived lectins that stimulate lymphocytes to enter mitosis induced human neutrophils to undergo NETosis, accumulate several molecular markers of mitosis, and duplicate their centrosomes despite these cells being terminally differentiated and unable to undergo mitosis. Induction of mitotic markers and centrosome duplication was also observed in the neutrophils of mice infected with Candida albicans and in tissue samples from human patients with fungal brain abscesses. The cell cycle inhibitor p21 suppressed NET formation, whereas the cyclin-dependent kinase CDK6 was required for NET formation by both human and mouse neutrophils in vitro. In a C. albicans sepsis model, Cdk6–/– mice exhibited earlier onset of symptoms, greater mortality, and increased fungal loads compared with wild-type mice. CDK4 was also present in neutrophils and transcriptionally induced during NETosis, suggesting that it may also play a role in NET formation. How these cell cycle regulators fit into the NETosis induction pathway was not fully characterized, but pharmacological inhibitors that target both CDK4 and CDK6 prevented the nuclear translocation of elastase without interfering with ROS generation or degranulation. These findings have potential implications for therapeutic strategies to limit NETosis in inflammatory diseases characterized by excessive NET formation, such as rheumatoid arthritis, lupus, and atherosclerosis (see also commentary by Albrengues et al.).

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