A Neutrophil Timer Coordinates Immune Defense and Vascular Protection

Immunity. 2019 Feb 19;50(2):390-402.e10. doi: 10.1016/j.immuni.2019.01.002. Epub 2019 Jan 29.


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.

Keywords: Bmal1; CXCR2; CXCR4; Candida albicans; Neutrophil; circadian clock; infection; inflammation; myocardial infarction; neutrophil aging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / immunology*
  • Blood Vessels / metabolism
  • Candida albicans / immunology
  • Candida albicans / physiology
  • Cells, Cultured
  • Cellular Senescence / immunology
  • Chemokine CXCL2 / immunology
  • Chemokine CXCL2 / metabolism
  • Circadian Rhythm / immunology*
  • Host-Pathogen Interactions / immunology
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration / immunology
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Neutrophils / microbiology
  • Phagocytosis / immunology*
  • Receptors, CXCR4 / immunology
  • Receptors, CXCR4 / metabolism
  • Time Factors


  • CXCR4 protein, human
  • Chemokine CXCL2
  • Receptors, CXCR4