IFN-γ mediates Paneth cell death via suppression of mTOR
- University of Rochester Medical Center, United States
- The Fox Chase Cancer Center, United States
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
Américo López-Yglesias
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).
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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IFN-γ mediates Paneth cell death via suppression of mTOR
eLife 10:e60478.
https://doi.org/10.7554/eLife.60478
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