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A circadian checkpoint relocates neutrophils to minimize injury

ABSTRACT: Inflammation-driven injury, a significant source of morbidity and mortality worldwide, is largely mediated by the cytotoxic activity of neutrophils, which extend the initial lesion and jeopardize organ function. Intriguingly, inflammatory injury naturally declines at specific times of day, suggesting that circadian mechanisms exist that mitigate the destructive activity of neutrophils and protect the host. Here, we show that the periods of diurnal protection coincide with peaks in plasma CXCL12, a chemokine that inhibits a neutrophil-intrinsic circadian clock by signaling through CXCR4. Genetic deletion of this clock, or a hyperactive form of CXCR4, prevented the diurnal spikes of injury, and treatment with a synthetic CXCR4 agonist conferred protection from myocardial and vascular occlusion. In tissues, this protection was mediated by repositioning neutrophils in the wound core, thus sparing neighboring host cells from death. Thus, a circadian neutrophil checkpoint protects from exuberant inflammatory injury and can be activated to protect the host.

ORGANISM(S): Mus musculus

PROVIDER: GSE304501 | GEO | 2025/11/11

REPOSITORIES: GEO

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