Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease
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Le résumé fourni par la source
BACKGROUND: Dysregulated inflammatory responses and oxidative stress are key pathogenic drivers of chronic inflammatory diseases such as liver cirrhosis (LC). Regulatory T cells (Tregs) are essential to prevent excessive immune activation and maintain tissue homeostasis. While inflammatory cues are well known to modulate the function and stability of Tregs, the extent to which Tregs are influenced by oxidative stress has not been fully explored. METHODS: Tregs isolated from patients with LC were compared to healthy controls (HC). Treg redox state was investigated by characterizing intracellular reactive oxygen species (ROS), NADPH oxidase-2 (Nox2) activity, mitochondrial function, morphology, and nuclear factor-erythroid 2-related factor (Nrf2) antioxidant signalling. The relevance of Nrf2 and its downstream target, Heme-oxygenase-1 (HO-1), in Treg function, stability, and survival, was further assessed using mouse models and CRISPR/Cas9-mediated HO-1 knock-out. FINDINGS: Circulating Tregs from LC patients displayed a reduced suppressive function, correlating with liver disease severity, associated with phenotypic abnormalities and increased apoptosis. Mechanistically, this was linked to a dysregulated Nrf2 signalling with resultant lower levels of HO-1, enhanced Nox2 activation, and impaired mitochondrial respiration and integrity. The functional deficit in LC Tregs could be partially recapitulated by culturing control Tregs in patient sera. INTERPRETATION: Our findings reveal that Tregs rely on functional redox homeostasis for their function, stability, and survival. Targeting Treg specific anti-oxidant pathways may have therapeutic potential to reverse the Treg impairment in conditions of oxidative damage such as advanced liver disease. FUNDING: This study was funded by the Wellcome Trust (211113/A/18/Z).
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease
- Date Crossref
- 01/09/2023
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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King's College London pays non établi dans la noticeUniversité ou école supérieure
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Guy's Hospital pays non établi dans la noticeÉtablissement de santé
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Bloomberg (United States) pays non établi dans la noticeEntreprise
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Johns Hopkins University Bloomberg-Kimmel Institute for Cancer Immunotherapy and Department of Oncology pays non établi dans la noticeUniversité ou école supérieure
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Sidney Kimmel Cancer Center pays non établi dans la noticeÉtablissement de santé
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Sidney Kimmel Comprehensive Cancer Center pays non établi dans la noticeStructure de recherche
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Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases pays non établi dans la noticeStructure de recherche
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Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas pays non établi dans la noticeStructure de recherche
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Max Planck Institute of Immunobiology and Epigenetics pays non établi dans la noticeStructure de recherche
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National Institute for Health and Care Research pays non établi dans la noticeOrganisme public
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NIHR Birmingham Biomedical Research Centre pays non établi dans la noticeStructure de recherche
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University of Birmingham Centre for Liver and Gastroenterology Research and Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre pays non établi dans la noticeUniversité ou école supérieure
King's College London, Guy's Hospital et Bloomberg (United States), avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.