Amit A. Patel 1 , Yan Zhang 2 , James N. Fullerton 1 , Lies Boelen 3 , Anthony Rongvaux 4 , Alexander A. Maini 1 , Venetia Bigley 6 , Richard A. Flavell 4 , 5 , Derek W. Gilroy 1 , Becca Asquith 3 , Derek Macallan 2 , 7 , Simon Yona , 1
03 July 2017
Using stable isotope labeling, Patel et al. establish the lifespan of all three human monocyte subsets that circulate in dynamic equilibrium; in steady state, classical monocytes are short-lived precursors with the potential to become intermediate and nonclassical monocytes. They highlight that systemic inflammation induces an emergency release of classical monocytes into the circulation.
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.