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Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin

Nature Immunology volume 18, pages 973984 (2017) | Download Citation

Abstract

The balance of myeloid populations and lymphoid populations must be well controlled. Here we found that osteopontin (OPN) skewed this balance during pathogenic conditions such as infection and autoimmunity. Notably, two isoforms of OPN exerted distinct effects in shifting this balance through cell-type-specific regulation of apoptosis. Intracellular OPN (iOPN) diminished the population size of myeloid progenitor cells and myeloid cells, and secreted OPN (sOPN) increase the population size of lymphoid cells. The total effect of OPN on skewing the leukocyte population balance was observed as host sensitivity to early systemic infection with Candida albicans and T cell–mediated colitis. Our study suggests previously unknown detrimental roles for two OPN isoforms in causing the imbalance of leukocyte populations.

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Acknowledgements

We thank M. Ciofani and M. Zuberbuehler for help in an experiment with fetal liver; M. Kondo for analysis of ex vivo progenitor-differentiation assays; G. Kucera for generating the LSL-iOPN bacterial artificial chromosome construct; the staff at the David H Murdock Research Institute for generating the sequence data; K. Abramson and E. Grass for generating the 10× single-cell libraries; and T. Kadota for help with in vitro experiments with BMMs in this study. Supported by the US National Institutes of Health (R01AI088100 and R21AI103584 to M.L.S.) and the US Department of Defense (PC100266 to M.L.S.).

Author information

Author notes

    • Masashi Kanayama
    •  & Makoto Inoue

    Present addresses: Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (M.K.), and Department of Comparative Biosciences, The University of Illinois at Urbana-Champaign, Urbana, Illinois, USA (M.I.).

    • Shengjie Xu
    •  & Keiko Danzaki

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.

    • Masashi Kanayama
    • , Shengjie Xu
    • , Keiko Danzaki
    • , Makoto Inoue
    •  & Mari L Shinohara
  2. Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.

    • Jason R Gibson
    •  & Simon G Gregory
  3. Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA.

    • Simon G Gregory
  4. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.

    • Mari L Shinohara

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Contributions

M.K. performed the majority of experiments; S.X. performed parts of the experiments assessing cell-density-mediated upregulation of OPN and confirmation of LSL-iOPN mice; K.D. performed parts of the BM-chimera experiments; J.R.G. and S.G.G. performed single-cell analysis, analyzed data and provided editorial help; M.I. provided experimental help in generating and confirming the LSL-iOPN mouse line; and M.K. and M.L.S. conceived of the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mari L Shinohara.

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DOI

https://doi.org/10.1038/ni.3791

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