Neutrophil ageing is regulated by the microbiome

Dachuan Zhang, Grace Chen, Deepa G. Manwani, Arthur Mortha, Chunliang Xu, Jeremiah J. Faith, Robert D. Burk, Yuya Kunisaki, Jung Eun Jang, Christoph Scheiermann, Miriam Merad, Paul S. Frenette

Research output: Contribution to journalArticle

191 Citations (Scopus)

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 α M β 2 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.

Original languageEnglish (US)
Pages (from-to)528-532
Number of pages5
JournalNature
Volume525
Issue number7570
DOIs
StatePublished - Sep 24 2015

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Microbiota
Neutrophils
Bone Marrow
Myeloid Differentiation Factor 88
CXCR4 Receptors
Stem Cell Niche
L-Selectin
Interleukin-17
Toll-Like Receptors
Sickle Cell Anemia
Granulocyte Colony-Stimulating Factor
Population Characteristics
Septic Shock
Hematopoietic Stem Cells
Endotoxins
Integrins
Up-Regulation
Inflammation

ASJC Scopus subject areas

  • General

Cite this

Zhang, D., Chen, G., Manwani, D. G., Mortha, A., Xu, C., Faith, J. J., ... Frenette, P. S. (2015). Neutrophil ageing is regulated by the microbiome. Nature, 525(7570), 528-532. https://doi.org/10.1038/nature15367

Neutrophil ageing is regulated by the microbiome. / Zhang, Dachuan; Chen, Grace; Manwani, Deepa G.; Mortha, Arthur; Xu, Chunliang; Faith, Jeremiah J.; Burk, Robert D.; Kunisaki, Yuya; Jang, Jung Eun; Scheiermann, Christoph; Merad, Miriam; Frenette, Paul S.

In: Nature, Vol. 525, No. 7570, 24.09.2015, p. 528-532.

Research output: Contribution to journalArticle

Zhang, D, Chen, G, Manwani, DG, Mortha, A, Xu, C, Faith, JJ, Burk, RD, Kunisaki, Y, Jang, JE, Scheiermann, C, Merad, M & Frenette, PS 2015, 'Neutrophil ageing is regulated by the microbiome', Nature, vol. 525, no. 7570, pp. 528-532. https://doi.org/10.1038/nature15367
Zhang D, Chen G, Manwani DG, Mortha A, Xu C, Faith JJ et al. Neutrophil ageing is regulated by the microbiome. Nature. 2015 Sep 24;525(7570):528-532. https://doi.org/10.1038/nature15367
Zhang, Dachuan ; Chen, Grace ; Manwani, Deepa G. ; Mortha, Arthur ; Xu, Chunliang ; Faith, Jeremiah J. ; Burk, Robert D. ; Kunisaki, Yuya ; Jang, Jung Eun ; Scheiermann, Christoph ; Merad, Miriam ; Frenette, Paul S. / Neutrophil ageing is regulated by the microbiome. In: Nature. 2015 ; Vol. 525, No. 7570. pp. 528-532.
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