Human neutrophil kinetics: a call to revisit old evidence

We posit that strict exponential loss of label in blood after reinfusion of 3H-labeled neutrophils in humans can be explained by the redistribution of labeled cells into a large neutrophil compartment in tissues, rather than by cell death.The lifespans and post-mitotic transfer times (PMTTs) of murine neutrophils are significantly shorter than those of human neutrophils, which precludes the direct translation of mouse data to humans.The long PMTT in humans precludes an effect of a circadian rhythm of neutrophil progenitors on the daily production and death of mature neutrophils.The mobilization by corticosteroids of extravasated labeled neutrophils in calves indicates that the disappearance of label of reinfused cells is not an indication of cell death.Current estimates of human neutrophil half-lives are based on assumptions for which experimental data are opposing or nonexisting.We propose that in homeostasis in humans, the oldest neutrophils are the first to die following a so-called conveyor belt model, as opposed to by random chance, as currently used in models estimating neutrophil half-lives. The correct interpretation of the available published data regarding the lifespan kinetics of the human neutrophil compartment is key for understanding the role of neutrophils in health and disease. The half-life of human neutrophils is still controversial, with estimates ranging from 7–9 h to 3.75 days. This debate should be settled to understand neutrophil production in the bone marrow (BM) and the potential and limitations of emergency neutropoiesis following infection or trauma. Furthermore, cellular lifespan greatly influences the potential effect(s) neutrophils have on the adaptive immune response. We posit that blood neutrophils are in exchange with different tissues, but particularly the BM, as it contains the largest pool of mature neutrophils. Furthermore, we propose that the oldest neutrophils are the first to die following a so-called conveyor belt model. These guiding principles shed new light on our interpretation of existing neutrophil lifespan data and offer recommendations for future research.