Journal
IMMUNITY
Volume 50, Issue 2, Pages 390-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2019.01.002
Keywords
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Categories
Funding
- A* STAR
- MEIC [SAF2014-61993-EXP, SAF2015-68632-R, SAF-2013-42920R, SAF2016-79040R, SAF2015-65607-R, SAF2013-49662-EXP, PCIN-2014-103]
- European Commission [635122-PROCROP H2020]
- European Research Council (ERC) [ERC CoG 725091]
- ERC [ERC AdG 692511 PROVASC]
- Deutsche Forschungsgemeinschaft [SFB1123-A1]
- German Center for Cardiovascular Research (DZHK) [MHA VD1.2/81Z1600212]
- Fondo de Investigaciones Sanitarias (FIS) [PI12/00494]
- Cardiovascular Network grant [RD 12/0042/0054, PI13/01979]
- CIBERCV
- Fondo Europeo de Desarrollo Regional (FEDER)
- Pro CNIC Foundation [SEV-2015-0505]
- Severo Ochoa Center of Excellence (MEIC) [PI13/01979]
- Ministerio de Economia, Industria y Competitividad
- MEIC [BES-2013-065550, BES-2010-032828, JCI-2012-14147]
- [SFB1123-A6]
- [SFB914-B08]
- [INST 211/604-2]
- [ZA 428/12-1]
- [ZA 428/13-1]
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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.
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