title: 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.
authors.affiliation: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany; Theoretical Immunology Group, Faculty of Medicine, Imperial College London, London, United Kingdom;
authors.forename: Julio
authors.initials: J
authors.lastname: Lahoz-Beneytez
authors.affiliation: Theoretical Immunology Group, Faculty of Medicine, Imperial College London, London, United Kingdom;
authors.forename: Marjet
authors.initials: M
authors.lastname: Elemans
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, United Kingdom; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, United Kingdom; and.
authors.forename: Raya
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, United Kingdom; and.
authors.forename: Arafa
authors.initials: A
authors.lastname: Salam
authors.affiliation: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Block
authors.affiliation: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Niederalt
authors.affiliation: Theoretical Immunology Group, Faculty of Medicine, Imperial College London, London, United Kingdom;
authors.forename: Becca
authors.identifier: 0000-0002-5911-3160
authors.initials: B
authors.lastname: Asquith
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, United Kingdom; and St George's University Hospitals NHS Foundation Trust, London, United Kingdom.
authors.forename: Derek
authors.identifier: 0000-0002-3014-7148
authors.initials: D
authors.lastname: Macallan
mesh_terms: D000328:Adult; D003903:Deuterium / Q000737:chemistry; D005260:Female; D005947:Glucose / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D042381:Granulocyte Precursor Cells / Q000166:cytology / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*
chemical_list: D003903:Deuterium; D005947:Glucose