Neutrophil ageing is regulated by the microbiome

Blood polymorphonuclear neutrophils provide immune protection against pathogens but also may promote tissue injury in inflammatory diseases(1,2). Although neutrophils are generally considered as a relatively homogeneous population, evidence for heterogeneity is emerging(3,4). Under steady-state conditions, neutrophil heterogeneity may arise from ageing and the replenishment by newly released neutrophils from the bone marrow(5). Aged neutrophils up-regulate CXCR4, a receptor allowing their clearance in the bone marrow(6,7), with feedback inhibition of neutrophil production via the IL17/G-CSF axis(8), and rhythmic modulation of the haematopoietic stem cell niche(5). The aged subset also expresses low levels of L-selectin (CD62L)(5,9). Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties(6,10). Here, we show using in vivo ageing analyses that the neutrophil pro-inflammatory activity correlates positively with their ageing in the circulation. Aged neutrophils represent an overly active subset exhibiting enhanced α(M)β(2) integrin (Mac-1) activation and neutrophil extracellular trap (NET) formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptors (TLRs)- and myeloid differentiation factor 88 (Myd88)-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 thus identify an unprecedented role for the microbiota in regulating a disease-promoting neutrophil subset.