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

eLife

David Stevenson¹  June Munro¹  Lynn McGarry¹  Sheila Bryson¹  Nicola Rath¹  Grant R Wickman²  Linda Julian²  Gregory Naylor²  Armandodel Del Río Hernández³  Alistair Rice³  Giovanni Castino⁴  Michael F Olson⁴  Margaret Mullin⁵ 

[1] Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom;Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom;Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, United Kingdom;Department of Chemistry and Biology, Ryerson University, Toronto, Canada;Electron Microscopy Facility, School of Life Sciences, University of Glasgow, Glasgow, United Kingdom;

关键词: apoptosis;    cytoskeleton;    signal transduction;    protein kinase;    Mouse;   

DOI  :  10.7554/eLife.61983

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY