Functional interaction between macrophages and hepatocytes dictate the outcome of liver fibrosis

Hepatocytes and liver-resident macrophages known as Kupffer cells (KCs) are key cell types involved in liver fibrosis. The transcription factor c-Jun plays a fundamental role in regulating hepatocyte and macrophage functions. We have examined c-Jun's role in the functional interaction of these cells during liver fibrosis induced by carbon tetrachloride. While hepatocyte-specific c-jun deletion led to increased fibrosis, the opposite outcome was observed when c-jun was deleted in both hepatocytes and KCs. Molecular analyses revealed compromised cytokine gene expression as the apical event related to the phenotype. Yet, purified hepatocytes from both mouse cohorts showed similar defects in cytokine gene expression. However, we noted increased macrophage infiltration in the absence of c-Jun in hepatocytes, which when chemically depleted, reversed the phenotype. Consistently, c-jun deletion in KCs alone also led to reduced fibrosis and cytokine gene expression. By contrast, c-jun deletion in hepatocytes and KCs did not affect the resolution phase after fibrotic injury. These data together demonstrate a pro-fibrogenic role for c-Jun in hepatocytes and KCs that functionally interact to regulate liver fibrosis.