TY - JOUR
T1 - Phosphatase and tensin homolog–β-catenin signaling modulates regulatory T cells and inflammatory responses in mouse liver ischemia/reperfusion injury
AU - Zhu, Qiang
AU - Li, Changyong
AU - Wang, Kunpeng
AU - Yue, Shi
AU - Jiang, Longfeng
AU - Ke, Michael
AU - Busuttil, Ronald W.
AU - Kupiec-Weglinski, Jerzy W.
AU - Zhang, Feng
AU - Lu, Ling
AU - Ke, Bibo
N1 - Publisher Copyright:
© 2017 by the American Association for the Study of Liver Diseases.
PY - 2017/6
Y1 - 2017/6
N2 - 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.
AB - 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.
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U2 - 10.1002/lt.24735
DO - 10.1002/lt.24735
M3 - Article
C2 - 28152578
AN - SCOPUS:85019897502
SN - 1527-6465
VL - 23
SP - 813
EP - 825
JO - Liver Transplantation
JF - Liver Transplantation
IS - 6
ER -