Editors' ChoiceCIRCADIAN REGULATION

The tick tock of toxicity

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Science Translational Medicine  12 Feb 2020:
Vol. 12, Issue 530, eabb1204
DOI: 10.1126/scitranslmed.abb1204

Abstract

A cell-intrinsic circadian program diminishes neutrophil toxicity to protect organs from excessive inflammation.

Neutrophils respond to infection by “arming” themselves with cytotoxic granules that can be wielded against pathogens. However, when these neutrophils migrate outside the vasculature, their inflammatory capabilities can also damage host tissues. This damage is particularly notable in pneumonia, the leading cause of death due to infection, where overzealous neutrophil activation can lead to significant tissue damage and death. Although cytotoxic granules are present from neutrophil maturation, homeostatic migration from the vasculature into organs does not lead to the same toxic effects noted during infection. However, the mechanism underlying this tissue protection was previously unknown.

Adrover et al. discovered that although these tissue-damaging granules are present at neutrophil genesis, the granules are shed via targeted modulations in the proteome before the homeostatic migration of neutrophils into organs. To validate this, they demonstrated that aged, granule-depleted neutrophils caused less vascular damage to mouse lungs than young, heavily granulated neutrophils. The shedding of granules prior to tissue entry was regulated by the circadian clock, and a knockout of the core clock protein Bmal1 eliminated the shedding of these granules. Their research suggested that this paradigm was conserved in humans, as they showed both oscillations in human neutrophil granulation as well as a peak in death of patients with severe pneumonia at the time when neutrophils were predicted to be equipped with the highest level of granule “ammunition.”

In conjunction with the authors’ previous study showing circadian timing of neutrophil aging, Adrover et al. highlight a circadian “program” that responds to external threats yet also reduces inflammatory damage, adding to the literature a mechanism that underlies the success of chronotherapeutic treatments. However, the intricacy of the response makes timing treatments based on this evidence complex, and only time will tell how this newfound knowledge might arm physicians treating pneumonia and other severe lung infections.

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