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A Neutrophil Timer Coordinates Immune Defense and Vascular Protection

2019; Cell Press; Volume: 50; Issue: 2 Linguagem: Inglês

10.1016/j.immuni.2019.01.002

1097-4180

José M. Adrover, Carlos del Fresno, Georgiana Crainiciuc, María Isabel Cuartero, María Casanova-Acebes, Linnea A. Weiss, Hector Huerga Encabo, Carlos Silvestre-Roig, Jan Rossaint, Itziar Cossío, Ana Victoria Lechuga‐Vieco, Jaime García‐Prieto, Mónica Gómez‐Parrizas, Juan A. Quintana, Iván Ballesteros, Sandra Martín-Salamanca, Alejandra Aroca-Crevillén, Shu Zhen Chong, Maximilien Evrard, Karl Balabanian, Jorge López López, Kiril Bidzhekov, Françoise Bachelerie, Francisco Abad‐Santos, Cecilia Muñoz‐Calleja, Alexander Zarbock, Oliver Soehnlein, Christian Weber, Lai Guan Ng, Cristina López‐Rodríguez, David Sancho, Marı́a A. Moro, Borja Ibáñez, Andrés Hidalgo,

Immune cells in cancer

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.