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.
Bibliographical noteFunding Information:
We would like to thank the all the volunteers who participated in this study, Jamie Evans (UCL) for his assistance with the cell sorting, and Jonathan Alderman (Yale University) for coordinating phlebotomy and logistics. We thank our colleagues for useful discussions, especially Dr. A. Mildner and Dr. S. Jung. A.A. Patel was supported by a PhD Studentship from the Engineering and Physical Sciences Research Council UK, and J.N. Fullerton was supported by the Wellcome Trust Clinical PhD Fellowship. D. Macallan received funding from the Medical Research Council UK (G1001052), The Wellcome Trust (project grant 093053/Z/10/Z), and Bloodwise (15012). B. Asquith is a Wellcome Trust Investigator (103865) and is funded by the Medical Research Council UK (J007439 and G1001052), the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement 317040 (QuanTI), and Leukemia and Lymphoma Research (15012). The authors declare no competing financial interests.
© 2017 Patel et al.