A circadian checkpoint relocates neutrophils to minimize injury

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. Overall design: To elucidate the transcriptional landscape of leukocyte heterogeneity during myocardial infarction in mice, we conducted single-cell RNA sequencing of DAPI-CD45+, DAPI-CD45-CD31+ and DAPI-CD45-CD31-PDGFRa+ cells obtained from control and infarcted heart of mice under different conditions. These conditions included vehicle-treated and ATI2341 treated mice, to elucidate the effect of a CXCR4 agonist (ATI2341) in leukocytes and other cell populations after an inflammatory insult such as myocardial infarction (45 min occlusion, 24h of reperfusion). Basal condition was also included as a control.