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

Autor:	Julian L; Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom.; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Naylor G; Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom.; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Wickman GR; Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom.; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Rath N; Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom., Castino G; Department of Chemistry and Biology, Ryerson University, Toronto, Canada., Stevenson D; Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom., Bryson S; Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom., Munro J; Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom., McGarry L; Cancer Research United Kingdom Beatson Institute, Garscube Estate, Glasgow, United Kingdom., Mullin M; Electron Microscopy Facility, School of Life Sciences, University of Glasgow, Glasgow, United Kingdom., Rice A; Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, United Kingdom., Del Río Hernández A; Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, United Kingdom., Olson MF; Department of Chemistry and Biology, Ryerson University, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Apr 19; Vol. 10. Date of Electronic Publication: 2021 Apr 19.
DOI:	10.7554/eLife.61983
Abstrakt:	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. Competing Interests: LJ, GN, GW, NR, GC, DS, SB, JM, LM, MM, AR, AD, MO No competing interests declared (© 2021, Julian et al.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu