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.
Highlights
Apoptotic cell death and the efficient clearance of cell corpses are essential for the normal development, growth and maintenance of every tissue in the human body (Elliott and Ravichandran, 2010; Boada-Romero et al, 2020)
It had previously been shown that a ROCK1 fragment equivalent to the caspase-cleaved form was more active than full-length protein (Coleman et al, 2001), and that the increased myosin light chains (MLCs) phosphorylation in apoptotic cells could be blocked by ROCK or caspase inhibitors (Sebbagh et al, 2001), direct ROCK1 activation solely by caspase cleavage had not been formally demonstrated
A recent study reported that ROCK2-specific activity was not affected by deletion of the C-terminal region (Truebestein et al, 2015), raising the possibility that in apoptotic cells ROCK1 cleavage plus an additional post-translational modification might be required for ROCK1 activation
Summary
Apoptotic cell death and the efficient clearance of cell corpses are essential for the normal development, growth and maintenance of every tissue in the human body (Elliott and Ravichandran, 2010; Boada-Romero et al, 2020). It has long been assumed that these apoptotic morphological changes are required for efficient clearance of apoptotic cell debris by phagocytic cells (Orlando et al, 2006; Wickman et al, 2012), and that they limit the release of cellular contents that could provoke acute inflammatory responses and the development of autoimmunity over time (Nagata et al, 2010) Consistent with this concept, defects in the recognition and clearance of apoptotic cells (Botto et al, 1998; Hanayama et al, 2004) result in autoimmune diseases in genetically modified mouse models.
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