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A Neutrophil Timer Coordinates Immune Defense and Vascular Protection

AuthorsAdrover, José M.; Fresno, Carlos del; Crainiciuc, Georgiana; Cuartero, Maria Isabel; Casanova-Acebes, María; Weiss, L.A.; Huerga-Encabo, Hector; Silvestre-Roig, C.; Rossaint, Jan; Cossío, Itziar; Lechuga-Vieco, Ana V.; García-Prieto, Jaime; Gómez-Parrizas, Mónica; Quintana, Juan A.; Ballesteros, Iván; Martin-Salamanca, Sandra; Aroca-Crevillen, Alejandra; Zhen Chong, Shu; Evrard, Maximilien; Balabanian, Karl; López, Jorge; Bidzhekov, Kiril; Bachelerie, Françoise; Abad-Santos, Francisco; Muñoz-Calleja, Cecilia; Zarbock, Alexander; Soehnlein, Oliver; Weber, C.; Guan Ng, Lai; Lopez-Rodriguez, Cristina; Sancho, David; Moro, María A.; Ibáñez, Borja; Hidalgo, Ándrés
Circadian clock
Myocardial infarction
Neutrophil aging
Candida albicans
Issue Date19-Feb-2019
CitationImmunity 50(2): 390-402.e10 (2019)
AbstractNeutrophils 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. Neutrophils display circadian oscillations in numbers and phenotype in the circulation. Adrover and colleagues now identify the molecular regulators of neutrophil aging and show that genetic disruption of this process has major consequences in immune cell trafficking, anti-microbial defense, and vascular health.
Publisher version (URL)http://dx.doi.org/10.1016/j.immuni.2019.01.002
Identifiersdoi: 10.1016/j.immuni.2019.01.002
issn: 1074-7613
e-issn: 1097-4180
Appears in Collections:(CNB) Artículos
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