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Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease.
Vaikunthanathan, Trishan; Landmann, Emmanuelle; Correa, Diana Marin; Romano, Marco; Trevelin, Silvia Cellone; Peng, Qi; Crespo, Elena; Corrado, Mauro; Lozano, Juan-José; Pearce, Erika L; Perpinan, Elena; Zoccarato, Anna; Siew, Leonard; Edwards-Hicks, Joy; Khan, Reenam; Luu, Nguyet-Thin; Thursz, Mark R; Newsome, Philip N; Martinez-Llordella, Marc; Shah, Naina; Lechler, Robert I; Shah, Ajay M; Sanchez-Fueyo, Alberto; Lombardi, Giovanna; Safinia, Niloufar.
Afiliação
  • Vaikunthanathan T; Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom. Electronic address: trishan.1.vaikunthanathan@kcl.ac.uk.
  • Landmann E; Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom. Electronic address: emmanuelle.1.landmann@kcl.ac.uk.
  • Correa DM; Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom. Electronic address: diana.marin_correa@kcl.ac.uk.
  • Romano M; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address: marco.romano@kcl.ac.uk.
  • Trevelin SC; Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom. Electronic address: silviacellone@outlook.com.
  • Peng Q; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address: qi.peng@kcl.ac.uk.
  • Crespo E; Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom. Electronic address: elena.crespo@kcl.ac.uk.
  • Corrado M; Bloomberg-Kimmel Institute for Cancer Immunotherapy and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: mcorrado@uni-koeln.de.
  • Lozano JJ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Joseph Stelzmannstrasse 26, 50931, Cologne, Germany. Electronic address: juanjo.lozano@ciberehd.org.
  • Pearce EL; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Calle Rossello 153 Bajos, O8036, Barcelona, Spain. Electronic address: epearce6@jhmi.edu.
  • Perpinan E; Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom. Electronic address: elena.perpinan_mas@kcl.ac.uk.
  • Zoccarato A; Department of Immunometabolism, Max Planck Institute of Immunobiology & Epigenetics, Stübeweg 51, 79108, Freiburg, Germany. Electronic address: anna.zoccarato@kcl.ac.uk.
  • Siew L; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address: leonard.siew@gstt.nhs.uk.
  • Edwards-Hicks J; Centre for Liver and Gastroenterology Research and Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom. Electronic address: je446@cam.ac.uk.
  • Khan R; Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, Liver Unit, 10th Floor QEQM Building, St Mary's Hospital, W2 1NY, London, United Kingdom. Electronic address: rsk409@student.bham.ac.uk.
  • Luu NT; Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, Liver Unit, 10th Floor QEQM Building, St Mary's Hospital, W2 1NY, London, United Kingdom. Electronic address: n.luu@bham.ac.uk.
  • Thursz MR; Institute of Liver Sciences, King's College Hospital NHS Foundation Trust, London, SE5 9NU, United Kingdom. Electronic address: m.thursz@imperial.ac.uk.
  • Newsome PN; Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, Liver Unit, 10th Floor QEQM Building, St Mary's Hospital, W2 1NY, London, United Kingdom. Electronic address: p.n.newsome@bham.ac.uk.
  • Martinez-Llordella M; Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom. Electronic address: marc.martinez-llordella@kcl.ac.uk.
  • Shah N; James Black Centre, Department of Cardiovascular sciences, British Heart Foundation Centre of Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, London, SE5 9NU, United Kingdom. Electronic address: naina.shah1@nhs.net.
  • Lechler RI; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address: robert.lechler@kcl.ac.uk.
  • Shah AM; Department of Immunometabolism, Max Planck Institute of Immunobiology & Epigenetics, Stübeweg 51, 79108, Freiburg, Germany. Electronic address: ajay.shah@kcl.ac.uk.
  • Sanchez-Fueyo A; Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom. Electronic address: sanchez_fueyo@kcl.ac.uk.
  • Lombardi G; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address: giovanna.lombardi@kcl.ac.uk.
  • Safinia N; Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom. Electronic address: niloufar.1.safinia@kcl.ac.uk.
EBioMedicine ; 95: 104778, 2023 Sep.
Article em En | MEDLINE | ID: mdl-37657135
ABSTRACT

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:

The phenotypic and functional properties of CD4+CD25+CD127lo/- 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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Hepatopatias / Antioxidantes Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Hepatopatias / Antioxidantes Idioma: En Ano de publicação: 2023 Tipo de documento: Article