Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation

Marlies Cortés (), Agnese Brischetto, M. C. Martinez-Campanario, Chiara Ninfali, Verónica Domínguez, Sara Fernández, Raquel Celis, Anna Esteve-Codina, Juan J. Lozano, Julia Sidorova, Gloria Garrabou, Anna-Maria Siegert, Carlos Enrich, Belén Pintado, Manuel Morales-Ruiz, Pedro Castro, Juan D. Cañete and Antonio Postigo ()
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Marlies Cortés: Cell Plasticity, Differentiation, and Cancer, IDIBAPS
Agnese Brischetto: Cell Plasticity, Differentiation, and Cancer, IDIBAPS
M. C. Martinez-Campanario: Cell Plasticity, Differentiation, and Cancer, IDIBAPS
Chiara Ninfali: Cell Plasticity, Differentiation, and Cancer, IDIBAPS
Verónica Domínguez: National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC/UAM-CBMSO) Transgenesis Facility, Higher Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco
Sara Fernández: Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER
Raquel Celis: Hospital Clínic and IDIBAPS
Anna Esteve-Codina: National Center for Genomics Analysis (CNAG)
Juan J. Lozano: Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute
Julia Sidorova: Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute
Gloria Garrabou: Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER
Anna-Maria Siegert: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Carlos Enrich: University of Barcelona School of Medicine and Health Sciences
Belén Pintado: National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC/UAM-CBMSO) Transgenesis Facility, Higher Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco
Manuel Morales-Ruiz: Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute
Pedro Castro: Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER
Juan D. Cañete: Hospital Clínic and IDIBAPS
Antonio Postigo: Cell Plasticity, Differentiation, and Cancer, IDIBAPS

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42277-4

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