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Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin

Nature Immunology volume 10, pages 734–743 (2009)Cite this article

Abstract

Macrophage colony-stimulating factor (M-CSF) influences the proliferation and survival of mononuclear phagocytes through the receptor CSF-1R. The adaptor protein DAP12 is critical for the function of mononuclear phagocytes. DAP12-mutant mice and humans have defects in osteoclasts and microglia, as well as brain and bone abnormalities. Here we show DAP12 deficiency impaired the M-CSF-induced proliferation and survival of macrophages in vitro. DAP12-deficient mice had fewer microglia in defined central nervous system areas, and DAP12-deficient progenitors regenerated myeloid cells inefficiently after bone marrow transplantation. Signaling by M-CSF through CSF-1R induced the stabilization and nuclear translocation of β-catenin, which activated genes involved in the cell cycle. DAP12 was essential for phosphorylation and nuclear accumulation of β-catenin. Our results provide a mechanistic explanation for the many defects of DAP12-deficient mononuclear phagocytes.

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Figure 1: Lower yield of DAP12-deficient BMDM cultures.
Figure 2: Impaired proliferation of DAP12-deficient BMDMs at day 5 of culture.
Figure 3: Impaired survival of DAP12-deficient BMDMs.
Figure 4: Loss of microglia in CNS of DAP12-deficient mice.
Figure 5: Defect in bone marrow repopulation by DAP12-deficient cells.
Figure 6: DAP12 deficiency augments M-CSF-induced MAPK activation.
Figure 7: M-CSF activates the β-catenin signaling pathway in a DAP12-dependent way.
Figure 8: DAP12-mediated tyrosine phosphorylation of β-catenin involves Pyk2.

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Acknowledgements

We thank D.M. Ornitz (Washington University School of Medicine) for the LEF-luc-pGL3 reporter plasmid; H.S. Earp III (University of North Carolina, Chapel Hill) for the plasmid encoding CRNK; T. Rolink (University of Basel) for IgM anti-CD4 and IgM anti-CD8; S. Gilfillan for critical reading of the manuscript; C. Laudanna and B. Rossi for advice on cell adhesion experiments; and Pfizer for the Pyk2 inhibitor PF 431396. Supported by the US National Institutes of Health (R01 GM077279 to M.C. and U54 AI1057160 to S.L.S.), Nobel Project Fondazione Cariplo (W.V.) and Fondazione Nocivelli (P.L.P.).

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  1. Taiki Aoshi

    Present address: Present address: Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka, Japan.,

Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Karel Otero, Isaiah R Turnbull, Elisa Cerutti, Taiki Aoshi, Ilaria Tassi, Mark Miller, Andrey S Shaw & Marco Colonna

  2. Department of Pathology, University of Brescia, Spedali Civili, Brescia, Italy

    Pietro Luigi Poliani & William Vermi

  3. Department of Experimental Immunology, Japan Science and Technology Agency, Tohoku University, Aoba-ku, Sendai-shi, Japan

    Toshiyuki Takai

  4. Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Samuel L Stanley

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Contributions

K.O. and I.R.T. designed and did experiments; P.L.P., W.V., T.A. and M.M. did and interpreted immunohistochemistry experiments; E.C., I.T. and A.S.S. did and interpreted adhesion assays and confocal microscopy studies; S.L.S. and T.T. provided reagents and expression data; and M.C. directed the research and wrote the paper.

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Correspondence to Marco Colonna.

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Otero, K., Turnbull, I., Poliani, P. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin. Nat Immunol 10, 734–743 (2009). https://doi.org/10.1038/ni.1744

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