Neutrophil ageing is regulated by the microbiome

Abstract

Blood polymorphonuclear neutrophils provide immune protection against pathogens but also may promote tissue injury in inflammatory diseases1,2. Although neutrophils are generally considered as a relatively homogeneous population, evidence for heterogeneity is emerging3,4. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and the replenishment by newly released neutrophils from the bone marrow5. Aged neutrophils up-regulate CXCR4, a receptor allowing their clearance in the bone marrow6,7, with feedback inhibition of neutrophil production via the IL17/G-CSF axis8, and rhythmic modulation of the haematopoietic stem cell niche5. 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 properties6,10. 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 αMβ2 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.

Neutrophils in cancer: neutral no more

“…Indeed, the phenotype and behavior of mature, aged neutrophils is not the same as young, newly released circulating neutrophils, even in tumor-free mice 76 . One explanation for the difference between immature and mature neutrophil function may be their distinctive composition of granules, because granules are synthesized at specific stages of neutrophil development 12 (Figure 1).…”

“…An example of this was shown in mice with chemically induced cancer crossed with histamine-deficient mice, where the lack of histamine stalled differentiation of immature neutrophils and increased tumor incidence and growth 75 . These data suggest that immature cells have independent functions from mature neutrophils.Indeed, the phenotype and behavior of mature, aged neutrophils is not the same as young, newly released circulating neutrophils, even in tumor-free mice 76 . One explanation for the difference between immature and mature neutrophil function may be their distinctive composition of granules, because granules are synthesized at specific stages of neutrophil development 12 (Figure 1).…”

Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis

“…9 Neutrophils that have resided longest in the bloodstream shed the surface selectin CD62L and enhance display of the chemokine receptor CXCR4, changes that precede extravasion and correspond with enhanced inflammatory capacity (termed neutrophil "aging"). 10,11 Simultaneously, accumulating oxidative damage and metabolic dysregulation cooperate to trigger spontaneous apoptosis among neutrophils upon their exit from the bloodstream. 12,13 Tight coordination of extravasion and cell death allows for efficient and immunologically quiescent clearance of expiring phagocytes.…”

Homeostatic migration and distribution of innate immune cells in primary and secondary lymphoid organs with ageing

“…Most authors believe that neutrophil numbers remain constant with ageing, although some authors reported reduced numbers [23]. With ageing, neutrophils have been implicated in the pathogenesis of Alzheimer's disease, atherosclerosis, cancer and autoimmune diseases [23], and a role of the microbiome has been implicated recently in neutrophil ageing, with a demonstration that neutrophil proinflammatory function in vivo correlates positively with age [24]. While GM-CSF promotes the chemotaxis of neutrophils in an adult animal, this is not the case in old Fig.…”