Defective apoptotic cell contractility provokes sterile inflammation leading to liver damage and tumour suppression
- Cancer Research UK Beatson Institute, United Kingdom
- Ryerson University, Canada
- University of Glasgow, United Kingdom
- 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.
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Author details
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.
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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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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