Phosphatase and tensin homolog-β-catenin signaling modulates regulatory T cells and inflammatory responses in mouse liver ischemia/reperfusion injury.
The phosphatase and tensin homolog (PTEN) deleted on chromosome 10 plays an important role in regulating T cell activation during inflammatory response. Activation of β-catenin is crucial for maintaining immune homeostasis. This study investigates the functional roles and molecular mechanisms by which PTEN-β-catenin signaling promotes regulatory T cell (Treg) induction in a mouse model of liver ischemia/reperfusion injury (IRI). We found that mice with myeloid-specific phosphatase and tensin homolog knockout (PTENM-KO) exhibited reduced liver damage as evidenced by decreased levels of serum alanine aminotransferase, intrahepatic macrophage trafficking, and proinflammatory mediators compared with the PTEN-proficient (floxed phosphatase and tensin homolog [PTENFL/FL]) controls. Disruption of myeloid PTEN-activated b-catenin promoted peroxisome proliferator-activated receptor gamma (PPARγ)-mediated Jagged-1/Notch signaling and induced forkhead box P3 (FOXP3)1 Tregs while inhibiting T helper 17 cells. However, blocking of Notch signaling by inhibiting γ-secretase reversed myeloid PTEN deficiency-mediated protection in ischemia/reperfusion-triggered liver inflammation with reduced FOXP3+and increased retinoid A receptor-related orphan receptor gamma t-mediated interleukin 17A expression in ischemic livers. Moreover, knockdown of β-catenin or PPARγ in PTEN-deficient macrophages inhibited Jagged-1/Notch activation and reduced FOXP3+Treg induction, leading to increased proinflammatory mediators in macrophage/T cell cocultures. In conclusion, our findings demonstrate that PTEN-β-catenin signaling is a novel regulator involved in modulating Treg development and provides a potential therapeutic target in liver IRI. Liver Transplantation 23 813-825 2017 AASLD.
Translational Research Medicine Center, Affiliated Jiangning Hospital, Nanjing Medical University, Nanjing, China.|Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China.|Children's Hospital, Nanjing Medical University, Nanjing, China.|The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA.
Qiang
Q
Zhu
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA.|Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
Changyong
C
Li
Translational Research Medicine Center, Affiliated Jiangning Hospital, Nanjing Medical University, Nanjing, China.|Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Kunpeng
K
Wang
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Shi
S
Yue
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA.
Longfeng
L
Jiang
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA.
Michael
M
Ke
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA.
Ronald W
RW
Busuttil
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA.
Jerzy W
JW
Kupiec-Weglinski
Translational Research Medicine Center, Affiliated Jiangning Hospital, Nanjing Medical University, Nanjing, China.|Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Feng
F
Zhang
Translational Research Medicine Center, Affiliated Jiangning Hospital, Nanjing Medical University, Nanjing, China.|Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Ling
L
Lu
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA.
Bibo
B
Ke
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006706:Homeostasis; D007249:Inflammation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D016031:Liver Transplantation; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D047495:PPAR gamma / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D047495:PPAR gamma; D051176:beta Catenin; D000410:Alanine Transaminase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse