Targeting TRAF3 signaling protects against hepatic ischemia/reperfusions injury.
OBJECTIVE
The hallmarks of hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, include severe cell death and inflammatory responses that contribute to early graft failure and a higher incidence of organ rejection. Unfortunately, effective therapeutic strategies are limited. Tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 3 transduces apoptosis and/or inflammation-related signaling pathways to regulate cell survival and cytokine production. However, the role of TRAF3 in hepatic I/R-induced liver damage remains unknown.


METHODS
Hepatocyte- or myeloid cell-specific TRAF3 knockdown or transgenic mice were subjected to an I/R model in vivo, and in vitro experiments were performed by treating primary hepatocytes from these mice with hypoxia/reoxygenation stimulation. The function of TRAF3 in I/R-induced liver damage and the potential underlying mechanisms were investigated through various phenotypic analyses and biological approaches.


RESULTS
Hepatocyte-specific, but not myeloid cell-specific, TRAF3 deficiency reduced cell death, inflammatory cell infiltration, and cytokine production in both in vivo and in vitro hepatic I/R models, whereas hepatic TRAF3 overexpression resulted in the opposite effects. Mechanistically, TRAF3 directly binds to TAK1, which enhances the activation of the downstream NF-κB and JNK pathways. Importantly, inhibition of TAK1 almost completely reversed the TRAF3 overexpression-mediated exacerbation of I/R injury.


CONCLUSIONS
TRAF3 is a novel hepatic I/R mediator that promotes liver damage and inflammation via TAK1-dependent activation of the JNK and NF-κB pathways. Inhibition of hepatic TRAF3 may represent a promising approach to protect the liver against I/R injury-related diseases.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
Junfei
J
Hu
Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xue-Hai
XH
Zhu
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Xiao-Jing
XJ
Zhang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
Pi-Xiao
PX
Wang
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Ran
R
Zhang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
Peng
P
Zhang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
Guang-Nian
GN
Zhao
Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Lu
L
Gao
College of Life Sciences, Wuhan University, Wuhan, China.
Xiao-Fei
XF
Zhang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
Song
S
Tian
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China. Electronic address: lihl@whu.edu.cn.
Hongliang
H
Li
D000818:Animals; D005260:Female; D006801:Humans; D008099:Liver / Q000098:blood supply*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D015427:Reperfusion Injury / Q000209:etiology* / Q000517:prevention & control; D048008:TNF Receptor-Associated Factor 3 / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D048008:TNF Receptor-Associated Factor 3; D000099151:MAP Kinase Kinase Kinase 7
Cell death; Hepatic ischemia/reperfusion; Inflammation; TAK1; TRAF3