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Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation
Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms sti...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10656499/ https://www.ncbi.nlm.nih.gov/pubmed/37978290 http://dx.doi.org/10.1038/s41467-023-42277-4 |
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author | Cortés, Marlies Brischetto, Agnese Martinez-Campanario, M. C. Ninfali, Chiara Domínguez, Verónica Fernández, Sara Celis, Raquel Esteve-Codina, Anna Lozano, Juan J. Sidorova, Julia Garrabou, Gloria Siegert, Anna-Maria Enrich, Carlos Pintado, Belén Morales-Ruiz, Manuel Castro, Pedro Cañete, Juan D. Postigo, Antonio |
author_facet | Cortés, Marlies Brischetto, Agnese Martinez-Campanario, M. C. Ninfali, Chiara Domínguez, Verónica Fernández, Sara Celis, Raquel Esteve-Codina, Anna Lozano, Juan J. Sidorova, Julia Garrabou, Gloria Siegert, Anna-Maria Enrich, Carlos Pintado, Belén Morales-Ruiz, Manuel Castro, Pedro Cañete, Juan D. Postigo, Antonio |
author_sort | Cortés, Marlies |
collection | PubMed |
description | Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression. |
format | Online Article Text |
id | pubmed-10656499 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-106564992023-11-17 Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation Cortés, Marlies Brischetto, Agnese Martinez-Campanario, M. C. Ninfali, Chiara Domínguez, Verónica Fernández, Sara Celis, Raquel Esteve-Codina, Anna Lozano, Juan J. Sidorova, Julia Garrabou, Gloria Siegert, Anna-Maria Enrich, Carlos Pintado, Belén Morales-Ruiz, Manuel Castro, Pedro Cañete, Juan D. Postigo, Antonio Nat Commun Article Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression. Nature Publishing Group UK 2023-11-17 /pmc/articles/PMC10656499/ /pubmed/37978290 http://dx.doi.org/10.1038/s41467-023-42277-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Cortés, Marlies Brischetto, Agnese Martinez-Campanario, M. C. Ninfali, Chiara Domínguez, Verónica Fernández, Sara Celis, Raquel Esteve-Codina, Anna Lozano, Juan J. Sidorova, Julia Garrabou, Gloria Siegert, Anna-Maria Enrich, Carlos Pintado, Belén Morales-Ruiz, Manuel Castro, Pedro Cañete, Juan D. Postigo, Antonio Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation |
title | Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation |
title_full | Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation |
title_fullStr | Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation |
title_full_unstemmed | Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation |
title_short | Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation |
title_sort | inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10656499/ https://www.ncbi.nlm.nih.gov/pubmed/37978290 http://dx.doi.org/10.1038/s41467-023-42277-4 |
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