PMID- 36070449
OWN - NLM
STAT- MEDLINE
DCOM- 20230321
LR  - 20240509
IS  - 1557-7716 (Electronic)
IS  - 1523-0864 (Print)
IS  - 1523-0864 (Linking)
VI  - 38
IP  - 7-9
DP  - 2023 Mar
TI  - CD4(+) T Cell NRF2 Signaling Improves Liver Transplantation Outcomes by 
      Modulating T Cell Activation and Differentiation.
PG  - 670-683
LID - 10.1089/ars.2022.0094 [doi]
AB  - Aims: Innate and adaptive immune responses regulate hepatic ischemia-reperfusion 
      injury (IRI) in orthotopic liver transplantation (OLT). While the mechanism of 
      how nuclear factor erythroid 2-related factor 2 (NRF2) plays a role in liver IRI 
      has been studied, the contribution of T cell-specific NRF2 in OLT remains 
      unknown. In the current translational study, we investigated whether and how 
      CD4(+) T cell-specific NRF2 signaling affects liver transplant outcomes in mice 
      and humans. Results: In the experimental arm, cold-stored (4 degrees C/18 h) wild-type 
      (WT) mouse livers transplanted to NRF2-deficient (NRF2-knockout [NRF2-KO]) 
      recipients experienced greater hepatocellular damage than those in 
      Nrf2-proficient (WT) counterparts, evidenced by Suzuki's histological scores, 
      frequency of TdT-mediated dUTP nick end labeling (TUNEL)(+) cells, and elevated 
      serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels. In 
      vitro studies showed that NRF2 signaling suppressed CD4(+) T cell differentiation 
      to a proinflammatory phenotype (Th1, Th17) while promoting the regulatory 
      (Foxp3(+)) T cell lineage. Furthermore, OLT injury deteriorated in 
      immune-compromised RAG2-KO test recipients repopulated with CD4(+) T cells from 
      NRF2-KO compared with WT donor mice. In the clinical arm of 45 human liver 
      transplant patients, the perioperative increase of NRF2 expression in donor 
      livers negatively regulated innate and adaptive immune activation, resulting in 
      reduced hepatocellular injury in NRF2-proficient OLT. Innovation and Conclusion: 
      CD4(+) T cell population expressing NRF2 attenuated ischemia and reperfusion 
      (IR)-triggered hepatocellular damage in a clinically relevant mouse model of 
      extended donor liver cold storage, followed by OLT, whereas the perioperative 
      increase of NRF2 expression reduced hepatic injury in human liver transplant 
      recipients. Thus, CD4(+) T cell NRF2 may be a novel cytoprotective sentinel 
      against IR stress in OLT recipients. Antioxid. Redox Signal. 38, 670-683.
FAU - Kojima, Hidenobu
AU  - Kojima H
AD  - The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver 
      and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los 
      Angeles, California, USA.
FAU - Kadono, Kentaro
AU  - Kadono K
AD  - The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver 
      and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los 
      Angeles, California, USA.
FAU - Hirao, Hirofumi
AU  - Hirao H
AD  - The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver 
      and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los 
      Angeles, California, USA.
FAU - Dery, Kenneth J
AU  - Dery KJ
AD  - The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver 
      and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los 
      Angeles, California, USA.
FAU - Kupiec-Weglinski, Jerzy W
AU  - Kupiec-Weglinski JW
AUID- ORCID: 0000-0001-8976-4872
AD  - The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver 
      and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los 
      Angeles, California, USA.
LA  - eng
GR  - P01 AI120944/AI/NIAID NIH HHS/United States
GR  - R01 DK062357/DK/NIDDK NIH HHS/United States
GR  - R01 DK102110/DK/NIDDK NIH HHS/United States
GR  - R01 DK107533/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
DEP - 20230301
PL  - United States
TA  - Antioxid Redox Signal
JT  - Antioxidants & redox signaling
JID - 100888899
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - *Liver Transplantation
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - T-Lymphocytes/metabolism
MH  - Living Donors
MH  - Liver/metabolism
MH  - *Liver Diseases/metabolism
MH  - CD4-Positive T-Lymphocytes
MH  - Cell Differentiation
MH  - *Reperfusion Injury/metabolism
MH  - Mice, Inbred C57BL
PMC - PMC10025842
OTO - NOTNLM
OT  - NRF2
OT  - T cell differentiation
OT  - liver ischemia-reperfusion injury
OT  - liver transplantation
OT  - translational research
COIS- The authors declare that they have no conflict of interest.
EDAT- 2022/09/08 06:00
MHDA- 2023/03/22 06:00
PMCR- 2024/03/01
CRDT- 2022/09/07 14:53
PHST- 2022/09/08 06:00 [pubmed]
PHST- 2023/03/22 06:00 [medline]
PHST- 2022/09/07 14:53 [entrez]
PHST- 2024/03/01 00:00 [pmc-release]
AID - 10.1089/ars.2022.0094 [pii]
AID - 10.1089/ars.2022.0094 [doi]
PST - ppublish
SO  - Antioxid Redox Signal. 2023 Mar;38(7-9):670-683. doi: 10.1089/ars.2022.0094. Epub 
      2023 Mar 1.