Neutrophil ageing is regulated by the microbiome

Neutrophil ageing, which encourages inflammation and vaso-occlusion in a mouse model of sickle-cell disease, is shown to depend on the intestinal microbiota and activation of the TLR/Myd88 signalling pathways. Neutrophils, the most abundant leukocyte type in the blood, are short-lived cells with an important role in innate immunity. However, activated neutrophils can also promote certain diseases by secreting pro-inflammatory cytokines. In cell culture, aged neutrophils have reduced migration and function. Paul Frenette and colleagues show here that neutrophils that have chronologically aged in the circulation are more active in promoting inflammation and contribute to vaso-occlusion in sickle cell disease in a mouse model. The authors show that neutrophil ageing is regulated by the microbiota through Toll-like receptors and the transcription factor Myd88. Microbiota depletion dramatically reduces the number of phenotypically aged neutrophils and their pro-inflammatory activities. 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 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.