Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.61983
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Funding
- Cancer Research UK [A10419, A17196, A18276]
- Canada Research Chairs [950-231665]
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2020-05388]
- Canadian Institutes of Health Research [PJT-169106]
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The activation of ROCK1 and consequent cell contraction are necessary to limit sterile inflammation and damage amplification following tissue-scale cell death. Inhibition of HMGB1 can reduce liver damage and neutrophil infiltration, while its inhibition can increase hepatocellular carcinoma development. Acute sterile inflammation also serves as an efficient tumor-suppressive mechanism.
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.
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