Format

Send to:

Choose Destination
See comment in PubMed Commons below
Nature. 2015 Sep 24;525(7570):528-32. doi: 10.1038/nature15367. Epub 2015 Sep 16.

Neutrophil ageing is regulated by the microbiome.

Author information

  • 1Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
  • 2Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
  • 3Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
  • 4Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
  • 5The Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
  • 6The Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
  • 7Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Abstract

Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis, and rhythmic modulation of the haematopoietic stem-cell niche. The aged subset also expresses low levels of L-selectin. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties. Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced αMβ2 integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.

Comment in

PMID:
26374999
[PubMed - indexed for MEDLINE]
PMCID:
PMC4712631
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Write to the Help Desk