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Origin of monocytes and macrophages in a committed progenitor

Nature Immunology volume 14, pages 821–830 (2013)Cite this article

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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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Figure 1: Identification of the cMoP in bone marrow by surface-marker expression and proliferative activity.
Figure 2: Identification of the cMoP in the spleen.
Figure 3: Colony formation, developmental origin and potential of the cMoP in vitro.
Figure 4: Developmental origin and potential of the cMoP in vivo.
Figure 5: Differentiation of macrophages from the cMoP in vivo.
Figure 6: Global proteomice analysis of the cMoP, the MDP and Ly6Chi monocytes.
Figure 7: Proteomics-based identification of phenotypic and functional differences among the MDP, the cMoP and Ly6Chi monocytes.
Figure 8: Expression of monocyte subset-specific genes in monocytes and their progenitors.

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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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Authors and Affiliations

  1. Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany

    Jan Hettinger, David M Richards, Melanie M Barra, Ann-Cathrin Joschko & Markus Feuerer

  2. Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany

    Jenny Hansson & Jeroen Krijgsveld

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Contributions

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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Correspondence to Markus Feuerer.

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Supplementary information

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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