Liver fibrosis is a wound healing process in case of repeated liver injury characterized by activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM). Depending on the duration and the nature of injury, liver fibrosis can be reversible; via elimination of activated HSCs and degradation of ECM. In contrast to chronic liver injury efficient liver regeneration occurs following acute liver injury without fibrosis development. However, little is known about the state of HSCs following acute liver injury. Here, our goal was to investigate HSCs dynamics during liver injury and regeneration and to identify the mechanisms that protect against liver fibrosis. For this purpose, mouse models of acute (single dose of acetaminophen or carbon tetrachloride, CCl4) and chronic (repeated CCl4 intoxication) liver injury were used. Induction of acute liver injury by APAP or CCl4 lead to massive killing of the pericentral hepatocytes. This was associated with massive activation and infiltration of HSCs into the dead cell area. However, these activated HSCs were efficiently eliminated within a week following liver injury without fibrosis development. In contrast, moderate cell killing and activation of HSCs following repeated liver injury lead to massive accumulation of ECM and fibrosis. Next, we investigated the mechanisms of activated HSCs elimination during liver recovery following acute and chronic damage scenarios. As already known, a fraction of activated HSCs reverts back to a quiescent phenotype during fibrosis recovery and a further fraction undergoes apoptosis. This effect was associated with massive infiltration of macrophages and NK cells. In contrast, although massive infiltration of macrophages was also observed following acute liver damage at the time when activated HSCs were eliminated, there was no reversion or apoptosis. It seems that activated HSCs are eliminated via direct engulfment by macrophages. This was supported by prolonged presence of activated HSCs after macrophage depletion. However, this prolonged preserve was transient, since activated HSCs were also eliminated within two weeks after induction of acute liver injury. Further analysis identified a backup mechanism of infiltrating immune cells (mainly B, T, NK and dendritic cells) which trigger apoptosis of activated HSCs in absence of macrophages. In conclusion, the efficient macrophage response following acute liver injury prevents liver fibrosis. When macrophages are eliminated a backup mechanism of infiltrating immune cells becomes active and triggers apoptosis of activated HSCs.
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