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Necroptosis in biliary atresia of the liver

Medical Molecular Morphology volume 54, pages 305–315 (2021)Cite this article

Abstract

Biliary atresia (BA) is characterized by the occlusion of extrahepatic bile ducts due to sclerosing inflammation. Necroptosis is a recently characterized form of programmed cell death but has not been examined in BA. We, therefore, explored the potential involvement of necroptosis in the pathogenesis of BA by evaluating the correlation between necroptosis-related factors and clinicopathological features of BA patients. We studied liver biopsy specimens of 59 patients with BA and 30 with congenital biliary dilatation (CBD). We also evaluated 14 surgical BA cases, who eventually underwent liver transplantation and 9 normal liver from neonates and infants obtained at autopsy. Necroptosis-related factors including toll-like receptor 3 (TLR3), receptor-interacting protein kinase1 (RIP1), receptor-interacting protein kinase3 (RIP3), mixed lineage kinase domain-like (MLKL), and phosphorylated mixed lineage kinase domain-like (pMLKL) in these liver specimens were immunolocalized. TLR3, RIP1, MLKL in the intrahepatic cholangiocytes was significantly higher in BA than CBD. pMLKL immunoreactivity was significantly greater at an earlier age of BA patients. The native liver survival period was significantly prolonged in the high RIP3 group. The low RIP3 status could serve as an adverse clinical prognostic factor for the native liver survival among the necroptosis-related factors examined in this study.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BA:

Biliary atresia

CBD:

Congenital biliary dilation

TLR3:

Toll-like receptor3

RIP1:

Receptor-interacting protein kinase1

RIP3:

Receptor-interacting protein kinase3

MLKL:

Mixed lineage kinase domain-like

pMLKL:

Phosphorylated mixed lineage kinase domain-like

DAMPs:

Danger-associated molecular patterns

TRIF:

TIR domain-containing adapter protein interferon-β

PBS:

Phosphate-buffered saline

H score:

Histological score

LI:

Labeling index

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Acknowledgements

We appreciate the skillful technical assistance of Ms. Yayoi Aoyama (Department of Pathology, Tohoku University Hospital, Sendai, Japan). We would like to thank Enago (www.enago.jp) for the English language review.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Masatoshi Hashimoto, Masaki Nio & Hironobu Sasano

  2. Department of Pathology, Tohoku University Graduate School of Medicine, 1-2 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Masatoshi Hashimoto & Fumiyoshi Fujishima

  3. Graduate Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Thanpisit Lomphithak

  4. Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Siriporn Jitkaew

  5. Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryou-machi, Aoba-Ku, Sendai, 980-8575, Japan

    Hironobu Sasano

Authors
  1. Masatoshi Hashimoto
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  2. Fumiyoshi Fujishima
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  3. Thanpisit Lomphithak
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  4. Siriporn Jitkaew
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  5. Masaki Nio
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Contributions

MH carried out an immunohistological examination. MH performed the statistical analysis. MH, FF, TL, SJ, MN, and HS conceived the study, participated in its design and coordination, and helped draft the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hironobu Sasano.

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Conflicts of interest

The authors have no conflicts of interest.

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of the Tohoku University School of Medicine (Accession No. 2019-1-470). Written informed consent was obtained from all patients prior to surgery.

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795_2021_289_MOESM1_ESM.docx

Supplementary file1 (DOCX 2164 KB) The receiver operating characteristics (ROC) curve against the native liver survival of the H-score and LI

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Hashimoto, M., Fujishima, F., Lomphithak, T. et al. Necroptosis in biliary atresia of the liver. Med Mol Morphol 54, 305–315 (2021). https://doi.org/10.1007/s00795-021-00289-3

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  • DOI: https://doi.org/10.1007/s00795-021-00289-3

Keywords

  • Biliary atresia
  • Congenital biliary dilation
  • Necroptosis
  • Cholangiocytes
  • Liver
  • Immunohistochemistry
  • Phosphorylated mixed lineage kinase domain-like
  • Cell death