2. Academic Validation
  3. Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis

Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis

  • Cell Death Dis. 2023 Mar 1;14(3):175. doi: 10.1038/s41419-023-05615-4.
Shen Yang # 1 2,  Na Chang # 1,  Weiyang Li # 1,  Ting Yang 2,  Renmin Xue 1,  Jing Liu 1,  Li Zhang 3,  Xingfeng Yao 4,  Yajun Chen 5,  Huanmin Wang 6,  Lin Yang 1,  Jinshi Huang 7,  Liying Li 8
Affiliations

Affiliations

  • 1 Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China.
  • 2 Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
  • 3 Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China.
  • 4 Department of Pathology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
  • 5 Department of General Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
  • 6 Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
  • 7 Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China. jsdr2002@126.com.
  • 8 Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China. liliying@ccmu.edu.cn.
  • # Contributed equally.
PMID: 36859525 DOI: 10.1038/s41419-023-05615-4
Abstract

Biliary atresia (BA) is a severe inflammatory and fibrosing neonatal cholangiopathy disease characterized by progressive obstruction of extrahepatic bile ducts, resulting in cholestasis and progressive hepatic failure. Cholestasis may play an important role in the inflammatory and fibrotic pathological processes, but its specific mechanism is still unclear. Necroptosis mediated by Z-DNA-binding protein 1 (ZBP1)/phosphorylated-mixed lineage kinase domain-like pseudokinase (p-MLKL) is a prominent pathogenic factor in inflammatory and fibrotic diseases, but its function in BA remains unclear. Here, we aim to determine the effect of macrophage Necroptosis in the BA pathology, and to explore the specific molecular mechanism. We found that Necroptosis existed in BA livers, which was occurred in liver macrophages. Furthermore, this process was mediated by ZBP1/p-MLKL, and the upregulated expression of ZBP1 in BA livers was correlated with liver fibrosis and prognosis. Similarly, in the bile duct ligation (BDL) induced mouse cholestatic liver injury model, macrophage Necroptosis mediated by ZBP1/p-MLKL was also observed. In vitro, conjugated bile acid-glycodeoxycholate (GDCA) upregulated ZBP1 expression in mouse bone marrow-derived monocyte/macrophages (BMDMs) through sphingosine 1-phosphate receptor 2 (S1PR2), and the induction of ZBP1 was a prerequisite for the enhanced Necroptosis. Finally, after selectively knocking down of macrophage S1PR2 in vivo, ZBP1/p-MLKL-mediated Necroptosis was decreased, and further collagen deposition was markedly attenuated in BDL mice. Furthermore, macrophage Zbp1 or Mlkl specific knockdown also alleviated BDL-induced liver injury/fibrosis. In conclusion, GDCA/S1PR2/ZBP1/p-MLKL mediated macrophage Necroptosis plays vital role in the pathogenesis of BA liver fibrosis, and targeting this process may represent a potential therapeutic strategy for BA.

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