1. Immunology and Inflammation
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IFN-γ mediates Paneth cell death via suppression of mTOR

  1. Alessandra Araujo
  2. Alexandra Safronova
  3. Elise Burger
  4. Américo López-Yglesias
  5. Shilpi Giri
  6. Ellie T Camanzo
  7. Andrew T Martin
  8. Sergei Grivennikov
  9. Felix Yarovinsky  Is a corresponding author
  1. University of Rochester Medical Center, United States
  2. The Fox Chase Cancer Center, United States
Research Article
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Cite this article as: eLife 2021;10:e60478 doi: 10.7554/eLife.60478

Abstract

Paneth cells constitutively produce antimicrobial peptides and growth factors that allow for intestinal homeostasis, host protection and intestinal stem cell replication. Paneth cells rely heavily on the glycolytic metabolic program, which is in part controlled by the kinase complex Mechanistic target of rapamycin (mTORC1). Yet, little is known about mTOR importance in Paneth cell integrity under steady state and inflammatory conditions. Our results demonstrate that IFN-γ, a crucial mediator of the intestinal inflammation, acts directly on murine Paneth cells to alter their mitochondrial integrity and membrane potential, resulting in an mTORC1-dependent cell death mechanism distinct from canonical cell death pathways including apoptosis, necroptosis, and pyroptosis. These results were established with the purified cytokine and a physiologically relevant common Th1-inducing human parasite Toxoplasma gondii. Given the crucial role for IFN-γ, which is a cytokine frequently associated with the development of inflammatory bowel disease (IBD) and compromised Paneth cell functions, the identified mechanisms underlying mTORC1-dependent Paneth cell death downstream of IFN-γ may provide promising novel approaches for treating intestinal inflammation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Alessandra Araujo

    University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7568-074X
  2. Alexandra Safronova

    University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Elise Burger

    University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Américo López-Yglesias

    University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6797-2179
  5. Shilpi Giri

    University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ellie T Camanzo

    University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Andrew T Martin

    University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sergei Grivennikov

    The Fox Chase Cancer Center, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Felix Yarovinsky

    University of Rochester Medical Center, Rochester, United States
    For correspondence
    felix_yarovinsky@URMC.Rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5825-8002

Funding

National Institutes of Health (R01AI136538)

  • Felix Yarovinsky

National Institutes of Health (R01AI121090)

  • Felix Yarovinsky

National Institutes of Health (CA218133)

  • Sergei Grivennikov

National Institutes of Health (CA227629)

  • Sergei Grivennikov

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

Ethics

Animal experimentation: All mice were maintained at in the pathogen-free American Association of Laboratory Animal Care-accredited animal facility at the University of Rochester Medical Center, Rochester, NY.All animal experimentation (animal protocol #102122) has been reviewed and approved by the University Committee on Animal Resources (UCAR).

Reviewing Editor

  1. Nicola L Harris, Monash University, Australia

Publication history

  1. Received: June 27, 2020
  2. Accepted: October 10, 2021
  3. Accepted Manuscript published: October 11, 2021 (version 1)

Copyright

© 2021, Araujo 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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