β-Catenin-NFkB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction

  1. Shikai Hu
  2. Jacquelyn O Russell
  3. Silvia Liu
  4. Catherine Cao
  5. Jackson McGaughey
  6. Ravi Rai
  7. Karis Kosar
  8. Junyan Tao
  9. Edward Hurley
  10. Minakshi Poddar
  11. Sucha Singh
  12. Aaron Bell
  13. Donghun Shin
  14. Reben Raeman
  15. Aatur D Singhi
  16. Kari Nejak-Bowen
  17. Sungjin Ko
  18. Satdarshan P Monga  Is a corresponding author
  1. Tsinghua University, China
  2. Boston Children's Hospital, United States
  3. University of Pittsburgh, United States

Abstract

Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of b-catenin, one with b-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived b-catenin-positive hepatocytes, and resolution of injury. KO1 showed persistent loss of b-catenin, NF-kB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of b-catenin, NFkB and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or b-catenin led to NF-kB activation, DR and inflammation. Thus, we report a novel b-catenin-NFkB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF.

Data availability

Raw RNA-seq data and gene count quantification were submitted to NCBI GEO data base with accession ID GSE155981

The following data sets were generated

Article and author information

Author details

  1. Shikai Hu

    Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Jacquelyn O Russell

    Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Silvia Liu

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Catherine Cao

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jackson McGaughey

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ravi Rai

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Karis Kosar

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Junyan Tao

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Edward Hurley

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Minakshi Poddar

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Sucha Singh

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Aaron Bell

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Donghun Shin

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7975-9014
  14. Reben Raeman

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Aatur D Singhi

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Kari Nejak-Bowen

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Sungjin Ko

    University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Satdarshan P Monga

    University of Pittsburgh, Pittsburgh, United States
    For correspondence
    smonga@pitt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8437-3378

Funding

National Institutes of Health (1R01DK62277,1R01DK100287,1R01DK116993,R01CA204586,1R01CA251155-01)

  • Satdarshan P Monga

National Institutes of Health (1R01CA258449)

  • Sungjin Ko

National Institutes of Health (T32EB0010216,1F31DK115017)

  • Jacquelyn O Russell

National Institutes of Health (P30DK120531)

  • Satdarshan P Monga

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved institutional animal care and use committee (IACUC) Protocol #: 19126451 of the University of Pittsburgh.

Human subjects: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of the University of Pittsburgh (STUDY19070068, STUDY20010114, and STUDY20040276 on 3/23/2021).

Reviewing Editor

  1. Paul W Noble, Cedars-Sinai Medical Centre, United States

Publication history

  1. Received: June 16, 2021
  2. Preprint posted: September 17, 2021 (view preprint)
  3. Accepted: October 1, 2021
  4. Accepted Manuscript published: October 5, 2021 (version 1)
  5. Version of Record published: October 29, 2021 (version 2)
  6. Version of Record updated: November 1, 2021 (version 3)

Copyright

© 2021, Hu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Shikai Hu
  2. Jacquelyn O Russell
  3. Silvia Liu
  4. Catherine Cao
  5. Jackson McGaughey
  6. Ravi Rai
  7. Karis Kosar
  8. Junyan Tao
  9. Edward Hurley
  10. Minakshi Poddar
  11. Sucha Singh
  12. Aaron Bell
  13. Donghun Shin
  14. Reben Raeman
  15. Aatur D Singhi
  16. Kari Nejak-Bowen
  17. Sungjin Ko
  18. Satdarshan P Monga
(2021)
β-Catenin-NFkB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction
eLife 10:e71310.
https://doi.org/10.7554/eLife.71310

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