Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation.
Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation is well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knockout (KO) resulted in liver protection from ischemia reperfusion injury (IRI) by deviating the local innate immune response against ischemia reperfusion toward the regulatory type: expression of proinflammatory genes was selectively decreased and anti-inflammatory IL-10 was simultaneously increased in ischemia reperfusion livers of PTEN KO mice compared with those of wild-type (WT) mice. PI3K inhibitor and IL-10-neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells and peritoneal macrophages isolated from KO mice expressed higher levels of M2 markers and produced lower TNF-α and higher IL-10 in response to TLR ligands than did their WT counterparts. They had enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation. Inactivation of Kupffer cells by gadolinium chloride enhanced proinflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation.
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
Shi
S
Yue
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.|Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiansu Province, China.
Jianhua
J
Rao
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.|Department of Liver Surgery, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Jianjun
J
Zhu
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
Ronald W
RW
Busuttil
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
Jerzy W
JW
Kupiec-Weglinski
Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiansu Province, China.
Ling
L
Lu
Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiansu Province, China.
Xuehao
X
Wang
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
Yuan
Y
Zhai
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D007728:Kupffer Cells / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050791:STAT Transcription Factors / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D057134:Antibodies, Neutralizing; C556062:IL10 protein, mouse; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse