Sabio lab

at the CNIO

Tag: alcohol

Predominantly pro-inflammatory phenotype with mixed M1/M2 polarization of peripheral blood classical monocytes and monocyte-derived macrophages among patients with excessive ethanol intake

07/09/2023 /

María Fernández-Regueras, Cristina Carbonell, Daniel Salete-Granado, Juan-Luis García, Marcos Gragera, María-Ángeles Pérez-Nieto, Francisco-Javier Morán-Plata, Andrea Mayado, Jorge-Luis Torres, Luis-Antonio Corchete, Ricardo Usategui-Martín, Elena Bueno-Martínez, Maura Rojas-Pirela, Guadalupe Sabio, Rogelio González-Sarmiento, Alberto Orfao, Francisco-Javier Laso, Julia Almeida & Miguel Marcos.

Excessive alcohol consumption impairs the immune system, induces oxidative stress, and triggers the activation of peripheral blood (PB) monocytes, thereby contributing to alcoholic liver disease (ALD).

miRNA of isolated CD14+ blood monocytes from excessive alcohol drinkers.

We analyzed the M1/M2 phenotypes of circulating classical monocytes and macrophage-derived monocytes (MDMs) in excessive alcohol drinkers (EADs). PB samples from 20 EADs and 22 healthy controls were collected for isolation of CD14+ monocytes and short-term culture with LPS/IFNγ, IL4/IL13, or without stimulation. These conditions were also used to polarize MDMs into M1, M2, or M0 phenotypes. Cytokine production was assessed in the blood and culture supernatants. M1/M2-related markers were analyzed using mRNA expression and surface marker detection. Additionally, the miRNA profile of CD14+ monocytes was analyzed. PB samples from EADs exhibited increased levels of pro-inflammatory cytokines. Following short-term culture, unstimulated blood samples from EADs showed higher levels of soluble TNF-α and IL-8, whereas monocytes expressed increased levels of surface TNF-α and elevated mRNA expression of pro-inflammatory cytokines and inducible nitric oxide synthase. MDMs from EADs showed higher levels of TNF-α and CD206 surface markers and increased IL-10 production. LPS/IFNγ induced higher mRNA expression of Nrf2 only in the controls. miRNA analysis revealed a distinctive miRNA profile that is potentially associated with liver carcinogenesis and ALD through inflammation and oxidative stress.

This study confirms the predominantly pro-inflammatory profile of PB monocytes among EADs and suggests immune exhaustion features in MDMs.

Antioxidants. 2023; 12 (9): 1708.

The outcome of boosting mitochondrial activity in alcoholic liver disease (ALD) is organ-dependent

08/02/2023 /

Naroa Goikoetxea-Usandizaga, Miren Bravo, Leire Egia-Mendikute, Leticia Abecia, Marina Serrano-Maciá, Rocío G Urdinguio, Marc Clos-García, Rubén Rodríguez-Agudo, Raquel Araujo-Legido, Lucía López-Bermudo, Teresa C Delgado, Sofía Lachiondo-Ortega, Irene González-Recio, Clàudia Gil-Pitarch, Ainize Peña-Cearra, Jorge Simón, Raquel Benedé-Ubieto, Silvia Ariño, Jose M Herranz, Mikel Azkargorta, Julio Salazar-Bermeo, Nuria Martí, Marta Varela-Rey, Juan M Falcón-Pérez, Óscar Lorenzo, Rubén Nogueiras, Félix Elortza Yulia A Nevzorova, Francisco J Cubero, Domingo Saura, Luis Alfonso Martínez-Cruz, Guadalupe Sabio, Asís Palazón, Pau Sancho-Bru, Natalia Elguezabal, Mario F Fraga, Matías A Ávila, Ramón Bataller, José J G Marín, Franz Martín & María Luz Martínez-Chantar.

Objective: Alcoholic liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help recovering mitochondrial fitness without collateral oxidative damage.

Design: C57BL/6 mice (Wild-type (Wt), Mcj knockout (MCJ-KO) and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, liver, gut, and pancreas where characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition.

Results: MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, i.e., mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD+/NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation.

Conclusion: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.

Hepatology 2023; doi: 10.1097/HEP.0000000000000303.

Fundación Princesa de Girona

Asociación Española Contra el Cáncer

Fundación BBVA

European Foundation for the Study of Diabetes

Immunothercan

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