Environmental stimuli shape microglial plasticity in glioma

  1. Stefano Garofalo
  2. Alessandra Porzia
  3. Fabrizio Mainiero
  4. Silvia Di Angelantonio
  5. Barbara Cortese
  6. Bernadette Basilico
  7. Francesca Pagani
  8. Giorgio Cignitti
  9. Giuseppina Chece
  10. Roberta Maggio
  11. Eve Tremblay
  12. Julie Savage
  13. Kanchan Bisht
  14. Vincenzo Esposito
  15. Giovanni Bernardini
  16. Thomas Seyfried
  17. Jakub Mieczkowski
  18. Karolina Stepniak
  19. Bozena Kaminska
  20. Angela Santoni
  21. Cristina Limatola  Is a corresponding author
  1. IRCCS Neuromed, Italy
  2. Sapienza University, Italy
  3. Consiglio Nazionale delle Ricerche, Italy
  4. Istituto Italiano di Tecnologia, Italy
  5. Université Laval, Canada
  6. Boston College, United States
  7. Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Poland

Abstract

In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, contributing to tumor growth and maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted. Modulation of gene expression depends on interferon-(IFN) g produced by natural killer (NK) cells, disappearing in mice depleted of NK cells or lacking IFN-g, and was mimicked by exogenous interleukin-15 (IL-15). Further, we describe a key role for BDNF produced in the brain of mice housed in EE in mediating the expression of IL-15 in CD11b+ cells. These data define novel mechanisms linking environmental cues to the acquisition of a pro-inflammatory, anti-tumor microenvironment in mouse brain.

Article and author information

Author details

  1. Stefano Garofalo

    IRCCS Neuromed, Pozzilli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  2. Alessandra Porzia

    IRCCS Neuromed, Pozzilli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  3. Fabrizio Mainiero

    Department of Experimental Medicine, Sapienza University, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Silvia Di Angelantonio

    Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1434-3648
  5. Barbara Cortese

    Institute of Nanotechnology, Consiglio Nazionale delle Ricerche, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Bernadette Basilico

    Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Francesca Pagani

    Center for Life Nanoscience, Istituto Italiano di Tecnologia, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Giorgio Cignitti

    Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Giuseppina Chece

    Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Roberta Maggio

    Department of Experimental Medicine, Sapienza University, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  11. Eve Tremblay

    Département de médecine moléculaire, Université Laval, Quebec City, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Julie Savage

    Département de médecine moléculaire, Université Laval, Quebec City, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Kanchan Bisht

    Département de médecine moléculaire, Université Laval, Quebec City, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Vincenzo Esposito

    IRCCS Neuromed, Pozzilli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  15. Giovanni Bernardini

    IRCCS Neuromed, Pozzilli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  16. Thomas Seyfried

    Biology department, Boston College, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Jakub Mieczkowski

    Neurobiology Center, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  18. Karolina Stepniak

    Neurobiology Center, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  19. Bozena Kaminska

    Neurobiology Center, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  20. Angela Santoni

    IRCCS Neuromed, Pozzilli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  21. Cristina Limatola

    IRCCS Neuromed, Pozzilli, Italy
    For correspondence
    cristina.limatola@uniroma1.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7504-8197

Funding

Associazione Italiana per la Ricerca sul Cancro (AIRC2015 IG16699)

  • Cristina Limatola

Ministero Istruzione Università Ricerca (PRIN 2015)

  • Cristina Limatola

CRCHU (Starting Grant)

  • Eve Tremblay

European Commission (Euronanomed2: Nanoglio)

  • Angela Santoni

Associazione Italiana per la Ricerca sul Cancro (AIRC2014 IG16014)

  • Angela Santoni

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The protocol was approved by the Ministry of Health of Italy in accordance with the guidelines on the ethical use of animals from the EC council directive of September 22, 2010 (2010/63/EU).

Reviewing Editor

  1. Serge Przedborski, Columbia University Medical Center, United States

Publication history

  1. Received: November 9, 2017
  2. Accepted: December 28, 2017
  3. Accepted Manuscript published: December 29, 2017 (version 1)
  4. Version of Record published: January 19, 2018 (version 2)

Copyright

© 2017, Garofalo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Stefano Garofalo
  2. Alessandra Porzia
  3. Fabrizio Mainiero
  4. Silvia Di Angelantonio
  5. Barbara Cortese
  6. Bernadette Basilico
  7. Francesca Pagani
  8. Giorgio Cignitti
  9. Giuseppina Chece
  10. Roberta Maggio
  11. Eve Tremblay
  12. Julie Savage
  13. Kanchan Bisht
  14. Vincenzo Esposito
  15. Giovanni Bernardini
  16. Thomas Seyfried
  17. Jakub Mieczkowski
  18. Karolina Stepniak
  19. Bozena Kaminska
  20. Angela Santoni
  21. Cristina Limatola
(2017)
Environmental stimuli shape microglial plasticity in glioma
eLife 6:e33415.
https://doi.org/10.7554/eLife.33415

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