A Neutrophil Timer Coordinates Immune Defense and Vascular Protection

Jose M. Adrover, Carlos del Fresno, Georgiana Crainiciuc, Maria Isabel Cuartero, Maria Casanova-Acebes, Linnea A. Weiss, Hector Huerga-Encabo, Carlos Silvestre-Roig, Jan Rossaint, Itziar Cossio, Ana V. Lechuga-Vieco, Jaime Garcia-Prieto, Monica Gomez-Parrizas, Juan A. Quintana, Ivan Ballesteros, Sandra Martin-Salamanca, Alejandra Aroca-Crevillen, Shu Zhen Chong, Maximilien Evrard, Karl BalabanianJorge Lopez, Kiril Bidzhekov, Frangoise Bachelerie, Francisco Abad-Santos, Cecilia Munoz-Calleja, Alexander Zarbock, Oliver Soehnlein, Christian Weber, Lai Guan Ng, Cristina Lopez-Rodriguez, David Sancho, Maria A. Moro, Borja Ibanez, Andres Hidalgo*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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. 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.

Original languageEnglish
Pages (from-to)390-402.e10
Number of pages23
JournalImmunity
Volume50
Issue number2
DOIs
Publication statusPublished - 19 Feb 2019

Keywords

  • FLUORESCENT PROTEIN
  • LEUKOCYTE ADHESION
  • BONE-MARROW
  • CXCR4
  • SELECTIN
  • INFLAMMATION
  • MODULATION
  • OSCILLATIONS
  • EXPRESSION
  • RELEASE

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