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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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/60478 |
| _version_ | 1811200746315579392 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T02:10:05Z |
| format | Article |
| id | doaj.art-532cf6093c7e4ab9ae8ce974e5157685 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:10:05Z |
| publishDate | 2021-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-532cf6093c7e4ab9ae8ce974e51576852022-12-22T03:52:26ZengeLife Sciences Publications LtdeLife2050-084X2021-10-011010.7554/eLife.60478IFN-γ mediates Paneth cell death via suppression of mTORAlessandra Araujo0https://orcid.org/0000-0001-7568-074XAlexandra Safronova1Elise Burger2Américo López-Yglesias3https://orcid.org/0000-0001-6797-2179Shilpi Giri4Ellie T Camanzo5Andrew T Martin6Sergei Grivennikov7Felix Yarovinsky8https://orcid.org/0000-0001-5825-8002Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, New York, United StatesCenter for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, New York, United StatesCenter for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, New York, United StatesCenter for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, New York, United StatesCenter for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, New York, United StatesCenter for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, New York, United StatesCenter for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, New York, United StatesDepartment of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States; Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, United StatesCenter for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, New York, United StatesPaneth 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.https://elifesciences.org/articles/60478IFN-gammaPaneth cellscell deathintestinemTORToxoplasma |
| spellingShingle | 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 eLife IFN-gamma Paneth cells cell death intestine mTOR Toxoplasma |
| title | 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_short | IFN-γ mediates Paneth cell death via suppression of mTOR |
| title_sort | ifn γ mediates paneth cell death via suppression of mtor |
| topic | IFN-gamma Paneth cells cell death intestine mTOR Toxoplasma |
| url | https://elifesciences.org/articles/60478 |
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