Phosphatase and tensin homolog–β‐catenin signaling modulates regulatory T cells and inflammatory responses in mouse liver ischemia/reperfusion injury. Issue 6 (June 2017)

• Record Type: Journal Article
• Authors: Zhu, Qiang; Li, Changyong; Wang, Kunpeng; Yue, Shi; Jiang, Longfeng; Ke, Michael; Busuttil, Ronald W.; Kupiec‐Weglinski, Jerzy W.; Zhang, Feng; Lu, Ling; Ke, Bibo
• Is Part Of: Liver transplantation. Volume 23:Issue 6(2017:Jun.)
• Page Start: 813
• Page End: 825
• Publication Date: 2017-06
• Subjects: Liver -- Transplantation -- Periodicals; Liver -- Diseases -- Periodicals; Liver Transplantation -- Periodicals; Foie -- Greffe -- Périodiques; 617.5560592
• DOI: 10.1002/lt.24735
• Languages: English
• ISSNs: 1527-6465

Abstract

Abstract : 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 (PTEN M‐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 [PTEN FL/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 .