PTEN-mediated Akt/β-catenin/Foxo1 signaling regulates innate immune responses in mouse liver ischemia/reperfusion injury.
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates innate immune responses inversely with phosphoinositide 3-kinase (PI3K) and its direct downstream target gene, Akt. The Forkhead box O (Foxo) transcription factors are essential in the regulation of tissue development, immune homeostasis, and cell survival. This study was designed to investigate the role of PTEN-mediated Akt/β-catenin/Foxo1 signaling in the regulation of in vivo and in vitro innate immune responses in a mouse model of hepatic inflammatory injury induced by 90 minutes of liver partial warm ischemia followed by 6 hours of reperfusion. We found that knockdown of PTEN with small interfering RNA (siRNA) promoted Akt/β-catenin/Foxo1 signaling, leading to resistance against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic function, and downregulation of innate Toll-like receptor 4 (TLR4) expression. A specific PI3K blockade inhibited Akt/β-catenin signaling, increased Foxo1-mediated TLR4-driven local inflammation, and recreated cardinal features of liver IR injury. Moreover, knockdown of PTEN in lipopolysaccharide-stimulated mouse bone marrow-derived macrophages enhanced β-catenin activity, which in turn provided a negative regulatory feedback to the Foxo1 function, leading to the inhibition of TLR4 and NF-κB, with ultimate depression of proinflammatory cytokine programs in vitro.


CONCLUSIONS
Our novel findings identify the PTEN-mediated Akt/β-catenin/Foxo1 axis as a key regulator of innate inflammatory response in the mouse liver. By identifying molecular mechanisms of PTEN-mediated Akt/β-catenin/Foxo1 signaling in TLR4 innate immune regulation, our study provides a rationale for therapeutic approaches to manage inflammation injury in IR-stressed liver.
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Naoko
N
Kamo
Bibo
B
Ke
Ronald W
RW
Busuttil
Jerzy W
JW
Kupiec-Weglinski
D000818:Animals; D017209:Apoptosis; D025461:Feedback, Physiological; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007113:Immunity, Innate; D056747:Immunomodulation; D008107:Liver Diseases / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse