Neutrophil ageing is regulated by the microbiome

• Autores: Dachuan Zhang, Grace Chen, Deepa Manwani, Arthur Mortha, Chunliang Xu, Jeremiah J. Faith, Robert D. Burk, Yuya Kunisaki, Jung-Eun Jang, Christoph Scheiermann, Miriam Merad, Paul S. Frenette
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 525, Nº 7570, 2015, págs. 528-532
• Idioma: inglés
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• Resumen

  • Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases1,2. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging3,4. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow5. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow6,7, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis8, and rhythmic modulation of the haematopoietic stem-cell niche5. The aged subset also expresses low levels of L-selectin5,9. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties6,10. 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 [alpha]M[beta]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.