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Adrover, Jose M.; del Fresno, Carlos; Crainiciuc, Georgiana; Isabel Cuartero, Maria; Casanova-Acebes, Maria; Weiss, Linnea A.; Huerga-Encabo, Hector; Silvestre-Roig, Carlos; Rossaint, Jan; Cossio, Itziar; Lechuga-Vieco, Ana V.; Garcia-Prieto, Jaime; Gomez-Parrizas, Monica; Quintana, Juan A.; Ballesteros, Ivan; Martin-Salamanca, Sandra; Aroca-Crevillen, Alejandra; Chong, Shu Zhen; Evrard, Maximilien; Balabanian, Karl; Lopez, Jörge; Bidzhekov, Kiril; Bachelerie, Frangoise; Abad-Santos, Francisco; Munoz-Calleja, Cecilia; Zarbock, Alexander; Soehnlein, Oliver; Weber, Christian; Ng, Lai Guan; Lopez-Rodriguez, Cristina; Sancho, David; Moro, Maria A.; Ibanez, Borja and Hidalgo, Andres (2019): A Neutrophil Timer Coordinates Immune Defense and Vascular Protection. In: Immunity, Vol. 50, No. 2

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Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.

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