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).

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.

Metrics

  • 2,374
    views
  • 437
    downloads
  • 55
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.33415

Further reading

    1. Neuroscience
    Julieta Gomez-Frittelli, Gabrielle Frederique Devienne ... Julia A Kaltschmidt
    Research Article

    Intrinsic sensory neurons are an essential part of the enteric nervous system (ENS) and play a crucial role in gastrointestinal tract motility and digestion. Neuronal subtypes in the ENS have been distinguished by their electrophysiological properties, morphology, and expression of characteristic markers, notably neurotransmitters and neuropeptides. Here, we investigated synaptic cell adhesion molecules as novel cell-type markers in the ENS. Our work identifies two type II classic cadherins, Cdh6 and Cdh8, specific to sensory neurons in the mouse colon. We show that Cdh6+ neurons demonstrate all other distinguishing classifications of enteric sensory neurons including marker expression of Calcb and Nmu, Dogiel type II morphology and AH-type electrophysiology and IH current. Optogenetic activation of Cdh6+ sensory neurons in distal colon evokes retrograde colonic motor complexes (CMCs), while pharmacologic blockade of rhythmicity-associated current IH disrupts the spontaneous generation of CMCs. These findings provide the first demonstration of selective activation of a single neurochemical and functional class of enteric neurons and demonstrate a functional and critical role for sensory neurons in the generation of CMCs.

    1. Neuroscience
    Damian Koevoet, Laura Van Zantwijk ... Christoph Strauch
    Research Article

    What determines where to move the eyes? We recently showed that pupil size, a well-established marker of effort, also reflects the effort associated with making a saccade (‘saccade costs’). Here, we demonstrate saccade costs to critically drive saccade selection: when choosing between any two saccade directions, the least costly direction was consistently preferred. Strikingly, this principle even held during search in natural scenes in two additional experiments. When increasing cognitive demand experimentally through an auditory counting task, participants made fewer saccades and especially cut costly directions. This suggests that the eye-movement system and other cognitive operations consume similar resources that are flexibly allocated among each other as cognitive demand changes. Together, we argue that eye-movement behavior is tuned to adaptively minimize saccade-inherent effort.