Mac the knife? Macrophages- the double-edged sword of hepatic fibrosis

Abstract

Progression of hepatic fibrosis requires sustained inflammation leading to activation of stellate cells into a fibrogenic and proliferative cell type, whereas regression is associated with stellate cell apoptosis. The contribution of hepatic macrophages to these events has been largely overlooked. However, a study in this issue of the JCI demonstrates that macrophages play pivotal but divergent roles, favoring ECM accumulation during ongoing injury but enhancing matrix degradation during recovery. These findings underscore the potential importance of hepatic macrophages in regulating both stellate cell biology and ECM degradation during regression of hepatic fibrosis.

Figure 1

Cellular events in hepatic fibrosis. As fibrosis develops in response to liver injury, stellate cell activation leads to accumulation of scar matrix. This in turn contributes to the loss of hepatocyte microvilli and endothelial fenestrae, which results in the deterioration of hepatic function. Kupffer cell (macrophage) activation contributes to the activation of stellate cells. Figure modified with permission from The Journal of Biological Chemistry (24).

Figure 2

The double-edged sword of hepatic macrophage activity in hepatic fibrosis progression versus recovery. The findings by Duffield et al. (4) in this issue of the JCI suggest that hepatic macrophages may induce divergent effects on liver fibrosis by promoting stellate cell activation in the face of continued injury and fibrosis; and stellate cell apoptosis during recovery associated with fibrosis regression as injury subsides. Evidence from other studies implicates TGF-β1 as one potential paracrine stimulator of stellate cell activation by macrophages, while TRAIL may mediate stellate cell apoptosis during fibrosis regression associated with recovery. Apoptosis associated with the loss of TIMP-1 may unmask latent matrix protease activity released by either macrophages, stellate cells, or other cell types. It is not certain if the same macrophages account for the divergent activities of this cell type or whether different macrophage subsets mediate these opposing pathways.