The fate and lifespan of human monocyte subsets in steady state and systemic inflammation

• Published in: The Journal of experimental medicine Vol. 214; no. 7; pp. 1913 - 1923
• Main Authors: Patel, Amit A., Zhang, Yan, Fullerton, James N., Boelen, Lies, Rongvaux, Anthony, Maini, Alexander A., Bigley, Venetia, Flavell, Richard A., Gilroy, Derek W., Asquith, Becca, Macallan, Derek, Yona, Simon
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 03.07.2017; The Rockefeller University Press
• Subjects: Animals; Bone marrow; Bone Marrow Cells - immunology; Cell Differentiation - immunology; Cell fate; Cell Survival - immunology; Cells, Cultured; Deuterium; Deuterium - metabolism; Endotoxemia; Endotoxemia - blood; Endotoxemia - immunology; Fate maps; Flow Cytometry; Homeostasis; Homeostasis - immunology; Human behavior; Humans; Inflammation; Inflammation - blood; Inflammation - immunology; Isotope Labeling - methods; Kinetics; Labeling; Life span; Mice; Monocytes; Monocytes - immunology; Repopulation; Restoration; Steady state; Time Factors
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20170355

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.