IFN-γ mediates Paneth cell death via suppression of mTOR

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 tar...

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Autores principales:	Alessandra Araujo, Alexandra Safronova, Elise Burger, Américo López-Yglesias, Shilpi Giri, Ellie T Camanzo, Andrew T Martin, Sergei Grivennikov, Felix Yarovinsky
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	IFN-gamma Paneth cells cell death intestine mTOR Toxoplasma Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/532cf6093c7e4ab9ae8ce974e5157685
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id	oai:doaj.org-article:532cf6093c7e4ab9ae8ce974e5157685
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spelling	oai:doaj.org-article:532cf6093c7e4ab9ae8ce974e51576852021-11-05T09:32:38ZIFN-γ mediates Paneth cell death via suppression of mTOR10.7554/eLife.604782050-084Xe60478https://doaj.org/article/532cf6093c7e4ab9ae8ce974e51576852021-10-01T00:00:00Zhttps://elifesciences.org/articles/60478https://doaj.org/toc/2050-084XPaneth 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 TORC1-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 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.Alessandra AraujoAlexandra SafronovaElise BurgerAmérico López-YglesiasShilpi GiriEllie T CamanzoAndrew T MartinSergei GrivennikovFelix YarovinskyeLife Sciences Publications LtdarticleIFN-gammaPaneth cellscell deathintestinemTORToxoplasmaMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	IFN-gamma Paneth cells cell death intestine mTOR Toxoplasma Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	IFN-gamma Paneth cells cell death intestine mTOR Toxoplasma Medicine R Science Q Biology (General) QH301-705.5 Alessandra Araujo Alexandra Safronova Elise Burger Américo López-Yglesias Shilpi Giri Ellie T Camanzo Andrew T Martin Sergei Grivennikov Felix Yarovinsky IFN-γ mediates Paneth cell death via suppression of mTOR
description	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 TORC1-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 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.
format	article
author	Alessandra Araujo Alexandra Safronova Elise Burger Américo López-Yglesias Shilpi Giri Ellie T Camanzo Andrew T Martin Sergei Grivennikov Felix Yarovinsky
author_facet	Alessandra Araujo Alexandra Safronova Elise Burger Américo López-Yglesias Shilpi Giri Ellie T Camanzo Andrew T Martin Sergei Grivennikov Felix Yarovinsky
author_sort	Alessandra Araujo
title	IFN-γ mediates Paneth cell death via suppression of mTOR
title_short	IFN-γ mediates Paneth cell death via suppression of mTOR
title_full	IFN-γ mediates Paneth cell death via suppression of mTOR
title_fullStr	IFN-γ mediates Paneth cell death via suppression of mTOR
title_full_unstemmed	IFN-γ mediates Paneth cell death via suppression of mTOR
title_sort	ifn-γ mediates paneth cell death via suppression of mtor
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/532cf6093c7e4ab9ae8ce974e5157685
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_version_	1718444288814088192

IFN-γ mediates Paneth cell death via suppression of mTOR

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