PMID- 37657135
OWN - NLM
STAT- MEDLINE
DCOM- 20230918
LR  - 20240508
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 95
DP  - 2023 Sep
TI  - Dysregulated anti-oxidant signalling and compromised mitochondrial integrity 
      negatively influence regulatory T cell function and viability in liver disease.
PG  - 104778
LID - S2352-3964(23)00344-4 [pii]
LID - 10.1016/j.ebiom.2023.104778 [doi]
LID - 104778
AB  - 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(+)CD127(lo/-) 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).
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Vaikunthanathan, Trishan
AU  - Vaikunthanathan T
AD  - 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.
FAU - Landmann, Emmanuelle
AU  - Landmann E
AD  - 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.
FAU - Correa, Diana Marin
AU  - Correa DM
AD  - 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.
FAU - Romano, Marco
AU  - Romano M
AD  - 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.
FAU - Trevelin, Silvia Cellone
AU  - Trevelin SC
AD  - 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.
FAU - Peng, Qi
AU  - Peng Q
AD  - 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.
FAU - Crespo, Elena
AU  - Crespo E
AD  - 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.
FAU - Corrado, Mauro
AU  - Corrado M
AD  - 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.
FAU - Lozano, Juan-Jose
AU  - Lozano JJ
AD  - Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated 
      Diseases (CECAD), Joseph Stelzmannstrasse 26, 50931, Cologne, Germany. Electronic 
      address: juanjo.lozano@ciberehd.org.
FAU - Pearce, Erika L
AU  - Pearce EL
AD  - Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas 
      (CIBEREHD), Calle Rossello 153 Bajos, O8036, Barcelona, Spain. Electronic 
      address: epearce6@jhmi.edu.
FAU - Perpinan, Elena
AU  - Perpinan E
AD  - 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.
FAU - Zoccarato, Anna
AU  - Zoccarato A
AD  - Department of Immunometabolism, Max Planck Institute of Immunobiology & 
      Epigenetics, Stubeweg 51, 79108, Freiburg, Germany. Electronic address: 
      anna.zoccarato@kcl.ac.uk.
FAU - Siew, Leonard
AU  - Siew L
AD  - 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.
FAU - Edwards-Hicks, Joy
AU  - Edwards-Hicks J
AD  - 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.
FAU - Khan, Reenam
AU  - Khan R
AD  - 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.
FAU - Luu, Nguyet-Thin
AU  - Luu NT
AD  - 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.
FAU - Thursz, Mark R
AU  - Thursz MR
AD  - Institute of Liver Sciences, King's College Hospital NHS Foundation Trust, 
      London, SE5 9NU, United Kingdom. Electronic address: m.thursz@imperial.ac.uk.
FAU - Newsome, Philip N
AU  - Newsome PN
AD  - 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.
FAU - Martinez-Llordella, Marc
AU  - Martinez-Llordella M
AD  - 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.
FAU - Shah, Naina
AU  - Shah N
AD  - 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.
FAU - Lechler, Robert I
AU  - Lechler RI
AD  - 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.
FAU - Shah, Ajay M
AU  - Shah AM
AD  - Department of Immunometabolism, Max Planck Institute of Immunobiology & 
      Epigenetics, Stubeweg 51, 79108, Freiburg, Germany. Electronic address: 
      ajay.shah@kcl.ac.uk.
FAU - Sanchez-Fueyo, Alberto
AU  - Sanchez-Fueyo A
AD  - 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.
FAU - Lombardi, Giovanna
AU  - Lombardi G
AD  - 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.
FAU - Safinia, Niloufar
AU  - Safinia N
AD  - 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.
LA  - eng
GR  - 211113/Z/18/Z/WT_/Wellcome Trust/United Kingdom
GR  - MR/S001581/1/MRC_/Medical Research Council/United Kingdom
GR  - RG/13/11/30384/BHF_/British Heart Foundation/United Kingdom
GR  - RG/20/3/34823/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
DEP - 20230830
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Antioxidants)
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Antioxidants
MH  - T-Lymphocytes, Regulatory
MH  - NF-E2-Related Factor 2
MH  - *Liver Diseases/etiology
MH  - Liver Cirrhosis
PMC - PMC10480539
OTO - NOTNLM
OT  - Liver cirrhosis
OT  - Mitochondria
OT  - Nrf2/heme oxygenase-1
OT  - Oxidative stress
OT  - Redox homeostasis
OT  - Regulatory T cells
COIS- Declaration of interests TV is currently employed by Janssen-Cilag Ltd (a 
      subsidiary of Johnson & Johnson) and owns Johnson & Johnson stock/stock options. 
      GL, ASF and MML are Founders of Quell Therapeutics Ltd. MR and MML are employed 
      by Quell Therapeutics Ltd. PN received funding from Novo Nordisk; is advisory 
      board member and received consulting fees from Novo Nordisk, Boehringer 
      Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, BMS, Pfizer, Sun Pharma, 
      Madrigal, GSK; speakers fees from Novo Nordisk, AiCME; and travel support from 
      Novo Nordisk. The authors declare that the research in this manuscript was 
      conducted in the absence of any commercial or financial relationships that could 
      be construed as a potential conflict of interest.
EDAT- 2023/09/02 05:42
MHDA- 2023/09/18 12:42
PMCR- 2023/08/30
CRDT- 2023/09/01 18:00
PHST- 2023/03/07 00:00 [received]
PHST- 2023/08/15 00:00 [revised]
PHST- 2023/08/15 00:00 [accepted]
PHST- 2023/09/18 12:42 [medline]
PHST- 2023/09/02 05:42 [pubmed]
PHST- 2023/09/01 18:00 [entrez]
PHST- 2023/08/30 00:00 [pmc-release]
AID - S2352-3964(23)00344-4 [pii]
AID - 104778 [pii]
AID - 10.1016/j.ebiom.2023.104778 [doi]
PST - ppublish
SO  - EBioMedicine. 2023 Sep;95:104778. doi: 10.1016/j.ebiom.2023.104778. Epub 2023 Aug 
      30.