Regulator of neutrophil’s microbe-trapping NETs revealed

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A new study was the end result of an international collaboration between researchers from Germany and the USA. Published in the journal Developmental Cell, the paper describes an important step in how neutrophil extracellular traps (NETs) are released.

“This is basically a type of beneficial cell suicide,” explained Borko Amulic, first author on the paper and a postdoc in the lab of Arturo Zychlinsky from the Max Planck Institute for Infection Biology (Berlin, Germany). “When neutrophils get overwhelmed, when they can no longer deal with a microbial threat by just engulfing it, that’s when the NETs are released.”

Once NET formation has been induced, a neutrophil will anchor itself to the surrounding tissues and break down its nuclear envelope. Zychlinsky and colleagues were intrigued by this behavior, as nuclear envelope breakdown only normally occurs during cell division.

Could it be that the same cell cycle proteins active during cell division were responsible for the release of these NETs?

To test this hypothesis the team inhibited cyclin-dependent kinases 4 and 6 (CDK4/6) in mouse neutrophils, observing a reduction in NET formation. Cdk6−/− mice subsequently displayed an impaired immune response when infected with Candida albicans.

The researchers demonstrated that NET production is induced by mitogens (a chemical substance that encourages cell division) and triggers multiple cell-cycle markers, such as phosphorylation of lamins and the retinoblastoma protein, the breakdown of the nuclear envelope and centrosome duplication.

“The ultimate goal for this research is to interfere clinically, either when too few or too many NETs are being produced,” concluded Amulic. “Also, this is just a really fascinating cell biological phenomenon.”

Sources: Amulic B, Knackstedt SL, Abed UA et al. Cell-cycle proteins control production of neutrophil extracellular traps. Dev. Cell. 43(4), 449–462 (2017); www.eurekalert.org/pub_releases/2017-11/cp-ccp112017.php

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