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

Elife. 2021 Apr 19:10:e61983. doi: 10.7554/eLife.61983.

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.

Keywords: apoptosis; cancer biology; cell biology; cytoskeleton; mouse; protein kinase; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Apoptosis*
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / prevention & control*
  • Caspases / metabolism
  • Cell Shape*
  • Chemical and Drug Induced Liver Injury / enzymology
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / pathology*
  • Diethylnitrosamine
  • Disease Models, Animal
  • Enzyme Activation
  • Glycyrrhizic Acid
  • HEK293 Cells
  • HMGB1 Protein / metabolism
  • Humans
  • Liver / enzymology
  • Liver / pathology*
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / pathology
  • Liver Neoplasms / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Mutation
  • Myosin Light Chains / metabolism
  • Neutrophil Infiltration
  • Phosphorylation
  • Sulfonamides
  • Toll-Like Receptor 4 / metabolism
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism*

Substances

  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Myosin Light Chains
  • Sulfonamides
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
  • Diethylnitrosamine
  • Glycyrrhizic Acid
  • Rock1 protein, mouse
  • rho-Associated Kinases
  • Caspases