Abstract
Monocytes, macrophages and dendritic cells (DCs) are developmentally related regulators of the immune system that share the monocyte-macrophage DC progenitor (MDP) as a common precursor. Unlike differentiation into DCs, the distal pathways for differentiation into monocytes and monocyte-derived macrophages are not fully elucidated. We have now demonstrated the existence of a clonogenic, monocyte- and macrophage-restricted progenitor cell derived from the MDP. This progenitor was a Ly6C+ proliferating cell present in the bone marrow and spleen that generated the major monocyte subsets and macrophages, but not DCs or neutrophils. By in-depth quantitative proteomics, we characterized changes in the proteome during monocyte differentiation, which provided insight into the molecular principles of developing monocytes, such as their functional maturation. Thus, we found that monocytes and macrophages were renewed independently of DCs from a committed progenitor.
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Acknowledgements
We thank A. Rudensky (Memorial Sloan-Kettering Cancer Center, New York) for B6N.129(Cg)-Foxp3tm3Ayr mice; M. Platten (German Cancer Research Center) for Cx3cr1-eGFP reporter mice; F. Rosenbauer and S. Ghani for help with the in vitro differentiation assay; the Central Animal Laboratory, Flow Cytometry and Light Microscopy core facilities of the German Cancer Research Center, as well as the European Molecular Biology Laboratory Proteomics Core Facility, for training and support; H.R. Rodewald, T. Feyerabend and B. Kyewski for support and discussions; P. Pyl for statistical advice; K. Lobbes, A. Schmälzle and C. Maul for technical support; and the Immunological Genome Project Consortium for assembled data35,44. Supported by the Helmholtz Association of German Research Centers (J.He. and M.M.B.; and HZ-NG-505 to M.F.) and the Netherlands Organization for Scientific Research (to J.K.).
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J.He., D.M.R., J.Ha., J.K. and M.F. designed experiments; J.He., D.M.R., J.Ha., M.M.B. and A.-C.J. did experiments; J.Ha. and J.K. did mass spectrometry; and J.He., D.M.R., J.Ha., M.M.B., J.K. and M.F. analyzed data and wrote the manuscript.
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Supplementary Figures and Tables
Supplementary Figures 1–8 and Supplementary Tables 1, 2, 5, 6 and 7 (PDF 2043 kb)
Supplementary Table 3
Full proteomics table for a total of 5967 proteins identified in the cMoP, MDP and Ly6Chigh monocyte proteome (XLSX 5235 kb)
Supplementary Table 4
GO process enrichment for comparison of the cMoP (upper part) and Ly6Chigh monocytes (lower part) (XLSX 39 kb)
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Hettinger, J., Richards, D., Hansson, J. et al. Origin of monocytes and macrophages in a committed progenitor. Nat Immunol 14, 821–830 (2013). https://doi.org/10.1038/ni.2638
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DOI: https://doi.org/10.1038/ni.2638
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