Cell-type-specific function of c-Jun N-terminal kinases (JNKs) determines the cholestasis activity in murine model

Background Cholestatic liver injury is a major cause of liver fibrosis in patients with chronic liver disease and is associated with c-Jun N-terminal kinases (JNK) activation. Earlier, Jnk1 and Jnk2 showed opposite functions in cholestasis models. While Jnk1^−/− mice were protected, Jnk2^−/− mice showed more fibrosis. However, the cell-specific function of JNKs during cholestasis has not been defined. Here, we investigated the cell-type-specific function of Jnk1 and/or Jnk2 for cholestasis.

Methods The relevance of JNK in human primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and murine cholestasis (BDL and Mdr2^-/- ) was tested. Wildtype (WT), hepatocyte-specific knockout mice for Jnk (Jnk1^Δhepa or Jnk2^Δhepa ) or Jnk1/2 (Jnk1^Δhepa/2^Δhepa ) were generated. Moreover, Jnk2^-/- and Jnk1^Δhepa/2^-/- mice were included. Mice were subjected to BDL for 28 days. Hepatic damage, cell death, proliferation, inflammation and fibrosis were assessed. Additionally, microarray analysis and bone marrow transplantation (BMT) were performed.

Results JNK is activated in human PSC and PBC livers compared to healthy controls and directly correlated with cholestatic disease activity. JNK activation was confirmed in murine cholestasis. After BDL, Jnk2^Δhepa mice showed the same levels of liver damage and fibrosis compared to WT controls. Conversely, lack of JNK activity in hepatocytes of Jnk1^Δhepa/2^Δhepa mice aggravated liver damage and fibrosis compared to WT controls. Increased hepatic cell death, proliferation, inflammation was characteristic in Jnk1^Δhepa/2^Δhepa livers. Moreover, additional deletion of Jnk2 in NPCs of Jnk2^-/- and Jnk1^Δhepa/2^-/- mice exacerbated the phenotype suggesting an additional protective role. Finally, BMT experiments excluded the role of Jnk2 in BM-derived cells in controlling BDL-dependent disease progression.

Conclusion JNK activation is characteristic in both hepatocytes and NPCs of human and experimental cholestasis. Combined but not individual function of Jnk1 and Jnk2 in hepatocytes is essential to protect against BDL-induced liver fibrosis. Jnk2 in NPCs but not BM-derived cells confers protection during cholestasis. Hence, our data provide cell-specific targets to develop new therapeutic avenues against cholestatic liver disease.

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Artikel online veröffentlicht:
07. September 2021