2. Academic Validation
  3. Treatment of acetaminophen-induced liver failure by blocking the death checkpoint protein TRAIL

Treatment of acetaminophen-induced liver failure by blocking the death checkpoint protein TRAIL

  • Biochim Biophys Acta Mol Basis Dis. 2020 Jan 1;1866(1):165583. doi: 10.1016/j.bbadis.2019.165583.
Qian Chen 1,  Dehong Yan 2,  Qingmei Zhang 3,  Guizhong Zhang 2,  Meng Xia 3,  Junxin Li 1,  Wugen Zhan 2,  Enyun Shen 3,  Zhihuan Li 4,  Lilong Lin 4,  Youhai H Chen 5,  Xiaochun Wan 6
Affiliations

Affiliations

  • 1 Shenzhen Laboratory of Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Shenzhen Laboratory of Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 3 Shenzhen Zhongke Amshenn Pharmaceutical Co., Shenzhen 518057, China.
  • 4 Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan 523000, China.
  • 5 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: yhc@pennmedicine.upenn.edu.
  • 6 Shenzhen Laboratory of Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen BinDeBioTech Co., Shenzhen 518055, China. Electronic address: xc.wan@siat.ac.cn.
PMID: 31676378 DOI: 10.1016/j.bbadis.2019.165583
Abstract

Acetaminophen (APAP) is one of the most commonly used drugs worldwide, and APAP-induced liver injury is the most frequent cause of acute liver failure in developed countries. However, the mechanisms of APAP-induced hepatotoxicity are not well understood, and treatment options for the disorder are very limited. Here, we show that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a major mediator of APAP-induced liver injury in mice, and its blockade markedly ameliorates the liver failure. In APAP-treated mice, TRAIL was expressed in the liver, spleen, and peripheral blood primarily by CD11b+Gr1+ neutrophils. The concentration of soluble TRAIL in the blood, and the frequencies of TRAIL+ leukocytes in the spleen and liver positively correlated with the severity of liver injury. APAP sensitized hepatocytes to TRAIL-induced Apoptosis by upregulating the expression of the TRAIL receptor DR5 (Death Receptor 5), presumably through its transcription factor CHOP (C/EBP homologous protein). Importantly, blocking TRAIL with a soluble DR5-Fc fusion protein (sDR5-Fc) significantly attenuated APAP-induced liver injury, the hepatic infiltration of leukocytes, the levels of inflammatory cytokines, and the mortality of mice. When administered alongside N-acetylcysteine, sDR5-Fc further protected against APAP-induced acute liver injury. Thus, the TRAIL-DR5 signaling pathway plays a key role in APAP-induced liver inflammation and failure, and its blockade represents an effective new strategy to treat the liver disease.

Keywords

Acetaminophen; DR5; Liver failure; Neutrophils; TRAIL.

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