Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation
-
Published:2023-11-17
Issue:1
Volume:14
Page:
-
ISSN:2041-1723
-
Container-title:Nature Communications
-
language:en
-
Short-container-title:Nat Commun
Author:
Cortés MarliesORCID, Brischetto AgneseORCID, Martinez-Campanario M. C.ORCID, Ninfali ChiaraORCID, Domínguez Verónica, Fernández Sara, Celis Raquel, Esteve-Codina Anna, Lozano Juan J., Sidorova Julia, Garrabou Gloria, Siegert Anna-MariaORCID, Enrich Carlos, Pintado Belén, Morales-Ruiz ManuelORCID, Castro PedroORCID, Cañete Juan D., Postigo AntonioORCID
Abstract
AbstractAcute 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.
Funder
LEO Pharma Research Foundation Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca Ministry of Economy and Competitiveness | Agencia Estatal de Investigación
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference66 articles.
1. Cecconi, M., Evans, L., Levy, M. & Rhodes, A. Sepsis and septic shock. Nature 392, 75–87 (2018). 2. Medzhitov, R. The spectrum of inflammatory responses. Nature 374, 1070–1075 (2021). 3. van der Poll, T., van de Veerdonk, F. L., Scicluna, B. P. & Netea, M. G. The immunopathology of sepsis and potential therapeutic targets. Nat. Rev. Immunol. 17, 407–420 (2017). 4. Fullerton, J. N. & Gilroy, D. W. Resolution of inflammation: a new therapeutic frontier. Nat. Rev. Drug Discov. 15, 551–567 (2016). 5. Cheng, S. C. et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 17, 406–413 (2016).
|
|