Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 7, Pages 1913-1923Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20170355
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Funding
- Engineering and Physical Sciences Research Council UK
- Wellcome Trust [093053/Z/10/Z]
- Medical Research Council UK [G1001052, J007439]
- Bloodwise [15012]
- Wellcome Trust Investigator [103865]
- Medical Research Council UK
- European Union Seventh Framework Program [317040]
- Leukemia and Lymphoma Research [15012]
- Engineering and Physical Sciences Research Council [1626362] Funding Source: researchfish
- Medical Research Council [MR/J007439/1, G1001052, G0601072] Funding Source: researchfish
- National Institute for Health Research [ACF-2010-18-029] Funding Source: researchfish
- Wellcome Trust [101155/Z/13/Z, 103865/Z/14/Z] Funding Source: researchfish
- Wellcome Trust [103865/Z/14/Z] Funding Source: Wellcome Trust
- MRC [MR/J007439/1, G1001052, G0601072] Funding Source: UKRI
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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 (similar to 4 and similar to 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.
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