Neutrophil ageing is regulated by the microbiome

Abstract

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 _Mβ 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.