Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives

Abstract

Human neutrophils have traditionally been thought to have a short half-life in blood; estimates vary from 4 to 18 hours. This dogma was recently challenged by stable isotope labeling studies with heavy water, which yielded estimates in excess of 3 days. To investigate this disparity, we generated new stable isotope labeling data in healthy adult subjects using both heavy water (n = 4) and deuterium-labeled glucose (n = 9), a compound with more rapid labeling kinetics. To interpret results, we developed a novel mechanistic model and applied it to previously published (n = 5) and newly generated data. We initially constrained the ratio of the blood neutrophil pool to the marrow precursor pool (ratio = 0.26; from published values). Analysis of heavy water data sets yielded turnover rates consistent with a short blood half-life, but parameters, particularly marrow transit time, were poorly defined. Analysis of glucose-labeling data yielded more precise estimates of half-life (0.79 ± 0.25 days; 19 hours) and marrow transit time (5.80 ± 0.42 days). Substitution of this marrow transit time in the heavy water analysis gave a better-defined blood half-life of 0.77 ± 0.14 days (18.5 hours), close to glucose-derived values. Allowing the ratio of blood neutrophils to mitotic neutrophil precursors (R) to vary yielded a best-fit value of 0.19. Reanalysis of the previously published model and data also revealed the origin of their long estimates for neutrophil half-life: an implicit assumption that R is very large, which is physiologically untenable. We conclude that stable isotope labeling in healthy humans is consistent with a blood neutrophil half-life of less than 1 day.

Neutrophils acquire the capacity for antigen presentation to memory CD4+ T cells in vitro and ex vivo

“…Recent findings indicate that the lifespan of neutrophils is not as short as previously thought. 35,36 We monitored the cell viability of neutrophils by using a live/dead dye at 4, 30, and 48 hours of culture post-flow cytometry sorting. Neutrophils showed similar viability to fresh cells for at least 30 hours whereas increased cell death was evident at 48 hours ( Figure 1D).…”

Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo

“…While the in vivo lifespan of neutrophils is unclear, recent evidence indicates that they have a half-life of as much as 13–19 hours (h) in blood7. Neutrophils during an inflammatory response have an extended lifespan compared to neutrophils in the blood in homeostasis8.…”

In vivo kinetics and nonradioactive imaging of rapidly proliferating cells in graft-versus-host disease

“…Additionally, we measured these processes in multiple anatomic compartments. Previous studies employed mathematical modeling to hypothesize in vivo cell kinetics outside of the circulation while measuring deuterium label gain and loss in circulating cells (18,19,21,22,24,27,30,(50)(51)(52)(53)(54). In contrast, we obtained quantitative measurements of deuterium gain and loss in T cell subsets from lymphoid and target organs, and we found the same subset (i.e., Treg) to behave differently in the spleen compared with the liver.…”

“…Pioneering in vivo kinetics studies were conducted in patients with HIV (18,19), which measured CD4 + and CD8 + T cell kinetics, and then in many other cell types and conditions (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). To date, studies involving stable water isotopes measured T cell kinetics in circulation, a dynamic cellular compartment, while systemic cell half-lives were mathematically estimated.…”