Cortes 2023 Nat Commun

Cortés M, Brischetto A, Martinez-Campanario MC, Ninfali C, Domínguez V, Fernández S, Celis R, Esteve-Codina A, Lozano JJ, Sidorova J, Garrabou G, Siegert AM, Enrich C, Pintado B, Morales-Ruiz M, Castro P, Cañete JD, Postigo A (2023) Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation. https://doi.org/10.1038/s41467-023-42277-4

» Nat Commun 14:7471. PMID: 37978290 Open Access

Cortes Marlies, Brischetto Agnese, Martinez-Campanario MC, Ninfali Chiara, Dominguez Veronica, Fernandez Sara, Celis Raquel, Esteve-Codina Anna, Lozano Juan J, Sidorova Julia, Garrabou Gloria, Siegert Anna-Maria, Enrich Carlos, Pintado Belen, Morales-Ruiz Manuel, Castro Pedro, Canete Juan D, Postigo Antonio (2023) Nat Commun

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.

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Labels: MiParea: Respiration 

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2023-11