Alejandra Aroca-Crevillén, Sandra Martín-Salamanca, Lidiane S. Torres, Georgiana Crainiciuc, Jon Sicilia, Eduardo Peñaloza-Martínez, Nicolás Rosillo, Miguel Molina-Moreno, José M. Adrover, Andrea Rubio-Ponce, Tommaso Vicanolo, Xiaosong Liu, Kanin Wichapong, Vanessa Núñez, Karl Balabanian, Françoise Bachelerie, David Sancho, María Casanova-Acebes, Jose T. Ortiz‐Pérez, Marı́a A. Moro, Héctor Bueno, Gerry A. F. Nicolaes, Andrés Hidalgo
Inflammation-driven injury, a significant source of morbidity and mortality worldwide, is largely mediated by the cytotoxic activities 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 the 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 injury. In tissues, this protection was mediated by repositioning neutrophils in the wound core, which spared neighboring host cells from apoptotic death. Thus, a circadian neutrophil checkpoint protects from exuberant inflammation and can be activated to protect the host.