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

155 Citations (Web of Science)

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.

Original languageEnglish
Pages (from-to)390-402
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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