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Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages

Nature Immunology volume 15, pages 10261037 (2014) | Download Citation

Abstract

Tissue-resident macrophages constitute heterogeneous populations with unique functions and distinct gene-expression signatures. While it has been established that they originate mostly from embryonic progenitor cells, the signals that induce a characteristic tissue-specific differentiation program remain unknown. We found that the nuclear receptor PPAR-γ determined the perinatal differentiation and identity of alveolar macrophages (AMs). In contrast, PPAR-γ was dispensable for the development of macrophages located in the peritoneum, liver, brain, heart, kidneys, intestine and fat. Transcriptome analysis of the precursors of AMs from newborn mice showed that PPAR-γ conferred a unique signature, including several transcription factors and genes associated with the differentiation and function of AMs. Expression of PPAR-γ in fetal lung monocytes was dependent on the cytokine GM-CSF. Therefore, GM-CSF has a lung-specific role in the perinatal development of AMs through the induction of PPAR-γ in fetal monocytes.

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Acknowledgements

We thank P. Chambon (Université Louis Pasteur) for Ppargfl/fl mice20; B. Becher (University of Zurich) for Csf2−/− and Csf2rb−/− mice; and C. Halin (Swiss Federal Institute of Technology Zurich) for Rosa26-stopflox-tdRFP mice43. Supported by the Swiss National Science Foundation (310030-124922/1) and Swiss Federal Institute of Technology Zurich (ETH-34 13-1).

Author information

Author notes

    • Christoph Schneider

    Present address: Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.

Affiliations

  1. Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland.

    • Christoph Schneider
    • , Samuel P Nobs
    •  & Manfred Kopf
  2. Pathology Institute, Zurich, Switzerland.

    • Michael Kurrer
  3. Functional Genomics Center, Zurich, Switzerland.

    • Hubert Rehrauer
  4. LIMES Institute, University of Bonn, Bonn, Germany.

    • Christoph Thiele

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Contributions

C.S. and M.Ko. designed the experiments; C.S. performed and analyzed most of the experiments; S.P.N., M.Ku., H.R. and C.T. performed and analyzed specific experiments; and C.S. and M.Ko. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Manfred Kopf.

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    Enrichment analysis in pathway maps for differentially expressed genes.

    Enrichment analysis was performed using MetaCore. List of 100 pathways enriched in differentially expressed genes are displayed for upregulated and downregulated genes (log2 ratio ≥1, P<0.05).

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DOI

https://doi.org/10.1038/ni.3005

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