Defective apoptotic cell contractility provokes sterile inflammation leading to liver damage and tumour suppression

  1. Linda Julian
  2. Gregory Naylor
  3. Grant R Wickman
  4. Nicola Rath
  5. Giovanni Costino
  6. David Stevenson
  7. Sheila Bryson
  8. June Munro
  9. Lynn McGarry
  10. Margaret Mullin
  11. Alistair Rice
  12. Armando del Río Hernández
  13. Michael F Olson  Is a corresponding author
  1. Cancer Research UK Beatson Institute, United Kingdom
  2. Ryerson University, Canada
  3. University of Glasgow, United Kingdom
  4. Imperial College London, United Kingdom

Abstract

Apoptosis is characterized by profound morphological changes, but their physiological purpose is unknown. To characterize the role of apoptotic cell contraction, ROCK1 was rendered caspase non-cleavable (ROCK1nc) by mutating Aspartate 1113, which revealed that ROCK1 cleavage was necessary for forceful contraction and membrane blebbing. When homozygous ROCK1nc mice were treated with the liver-selective apoptotic stimulus of diethylnitrosamine, ROCK1nc mice had more profound liver damage with greater neutrophil infiltration than wild-type mice. Inhibition of the damage associated molecular pattern protein HMGB1 or signalling by its cognate receptor TLR4 lowered neutrophil infiltration and reduced liver damage. ROCK1nc mice also developed fewer diethylnitrosamine-induced hepatocellular carcinoma (HCC) tumours, while HMGB1 inhibition increased HCC tumour numbers. Thus, ROCK1 activation and consequent cell contraction are required to limit sterile inflammation and damage amplification following tissue-scale cell death. Additionally, these findings reveal a previously unappreciated role for acute sterile inflammation as an efficient tumour suppressive mechanism.

Data availability

Data generated during this study are presented in the figures. No datasets were generated or used in this study.

Article and author information

Author details

  1. Linda Julian

    Molecular Cell Biology, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Gregory Naylor

    Molecular Cell Biology, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Grant R Wickman

    Molecular Cell Biology, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Nicola Rath

    Molecular Cell Biology, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Giovanni Costino

    Chemistry and Biology, Ryerson University, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. David Stevenson

    Transgenic Technology, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Sheila Bryson

    Molecular Cell Biology, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. June Munro

    Molecular Cell Biology, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Lynn McGarry

    High-Content Analysis Resource, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7055-2615
  10. Margaret Mullin

    School of Life Sciences, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Alistair Rice

    Department of Bioengineering, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Armando del Río Hernández

    Department of Bioengineering, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Michael F Olson

    Chemistry and Biology, Ryerson University, Toronto, Canada
    For correspondence
    michael.olson@ryerson.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3428-3507

Funding

Cancer Research UK (A10419)

  • Linda Julian
  • Gregory Naylor
  • Grant R Wickman
  • Nicola Rath
  • David Stevenson
  • Sheila Bryson
  • June Munro
  • Lynn McGarry
  • Michael F Olson

Cancer Research UK (A17196)

  • Linda Julian
  • Gregory Naylor
  • Grant R Wickman
  • Nicola Rath
  • David Stevenson
  • Sheila Bryson
  • June Munro
  • Lynn McGarry
  • Michael F Olson

Cancer Research UK (A18276)

  • Linda Julian
  • Gregory Naylor
  • Grant R Wickman
  • Nicola Rath
  • Michael F Olson

Canada Research Chairs (950-231665)

  • Michael F Olson

Natural Sciences and Engineering Research Council of Canada (RGPIN-2020-05388)

  • Giovanni Costino
  • Michael F Olson

Canadian Institutes of Health Research (PJT-169106)

  • Giovanni Costino
  • Michael F Olson

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

Ethics

Animal experimentation: All mouse experiments were approved by the University of Glasgow College of Medicine, Veterinary and Life Sciences Research Ethics Committee, and performed under a project license granted by the United Kingdom government Home Office, in line with the Animals (Scientific Procedures) Act 1986 and European Union Directive 2010/63/EU in a dedicated barriered facility.

Reviewing Editor

  1. Carla V Rothlin, Yale School of Medicine, United States

Publication history

  1. Received: August 11, 2020
  2. Accepted: April 17, 2021
  3. Accepted Manuscript published: April 19, 2021 (version 1)
  4. Version of Record published: April 30, 2021 (version 2)

Copyright

© 2021, Julian 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. Linda Julian
  2. Gregory Naylor
  3. Grant R Wickman
  4. Nicola Rath
  5. Giovanni Costino
  6. David Stevenson
  7. Sheila Bryson
  8. June Munro
  9. Lynn McGarry
  10. Margaret Mullin
  11. Alistair Rice
  12. Armando del Río Hernández
  13. Michael F Olson
(2021)
Defective apoptotic cell contractility provokes sterile inflammation leading to liver damage and tumour suppression
eLife 10:e61983.
https://doi.org/10.7554/eLife.61983

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