Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7864
A Neutrophil Timer Coordinates Immune Defense and Vascular Protection
Adrover, Jose M CNIC | del Fresno, Carlos CNIC | Crainiciuc, Georgiana CNIC | Cuartero, Maria Isabel | Casanova-Acebes, Maria CNIC | Weiss, Linnea A CNIC | Huerga-Encabo, Hector | Silvestre-Roig, Carlos CNIC | Rossaint, Jan | Cossio, Itziar CNIC | Lechuga-Vieco, Ana V. CNIC | Garcia-Prieto, Jaime CNIC | Gomez-Parrizas, Monica CNIC | Quintana, Juan A. CNIC | Ballesteros, Ivan CNIC | Martin-Salamanca, Sandra CNIC | Aroca-Crevillen, Alejandra CNIC | Chong, Shu Zhen | Evrard, Maximilien | Balabanian, Karl | López, Jorge | Bidzhekov, Kiril | Bachelerie, Françoise | Abad-Santos, Francisco | Muñoz-Calleja, Cecilia | Zarbock, Alexander | Soehnlein, Oliver | Weber, Christian | Ng, Lai Guan | Lopez-Rodriguez, Cristina | Sancho, David CNIC | Moro, María A. | Ibanez, Borja CNIC | Hidalgo, Andrés CNIC
Immunity. 2019; 50(2):390-402
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.
Bmal1 | CXCR2 | CXCR4 | Candida albicans | Neutrophil | circadian clock | infection | inflammation | myocardial infarction | neutrophil aging
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