Z Gastroenterol 2021; 59(01): e5
DOI: 10.1055/s-0040-1721953
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JNK mediates differential protection in hepatocytes and non-parenchymal cells during cholestasis

MR Mohamed
1   University Hospital, RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
2   National Research Centre, Department of Therapeutic Chemistry, Cairo, Egypt
,
G Zhao
1   University Hospital, RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
,
YA Nevzorova
1   University Hospital, RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
3   12 de Octubre Health Research Institute (imas12), Madrid, Spain
4   Complutense University School of Medicine, Department of Immunology, Ophthalmology & ENT, Madrid, Spain
,
J Haybaeck
5   Medical University of Innsbruck, Department of Pathology, Neuropathology and Molecular Pathology, Innsbruck, Austria
6   Medical University of Graz, Diagnostic and Research Center for Molecular BioMedicine, Institute of Pathology, Graz, Austria
7   Medical Faculty, Otto-von-Guericke University Magdeburg, Department of Pathology, Magdeburg, Germany
,
MV Boekschoten
8   Wageningen University, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen, Netherlands
,
P Boor
9   University Hospital, RWTH Aachen, Institute of Pathology & Department of Nephrology, Aachen, Germany
,
P Strnad
1   University Hospital, RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
,
JP Sarges
1   University Hospital, RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
,
RJ Davis
10   University of Massachusetts Medical School, Howard Hughes Medical Institute, Massachusetts, United States
,
FJ Cubero
1   University Hospital, RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
3   12 de Octubre Health Research Institute (imas12), Madrid, Spain
4   Complutense University School of Medicine, Department of Immunology, Ophthalmology & ENT, Madrid, Spain
,
C Trautwein
1   University Hospital, RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
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Background Chronic cholestasis triggers severe liver injury, inflammation and subsequently liver fibrosis associated with c-Jun N-terminal kinases (JNK) activation. However, the JNK specific role during cholestasis in parenchymal and non-parenchymal cells (NPCs) has not been defined yet. Previously, we demonstrated that Jnk1 in hepatocytes has no impact on chronic hepatic injury during experimental fibrosis. Here, we investigated the relevance of Jnk2 but also Jnk1 and Jnk2 specifically in hepatocytes and NPCs for cholestatic liver fibrosis.

Methods JNK activation was investigated in patients with cholestatic liver disease namely primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) (n = 27). Wildtype (WT), hepatocyte-specific knockout mice for Jnk2 (Jnk2Δhepa ) or Jnk1 and Jnk2 (Jnk1Δhepa/2Δhepa ) were generated. Additionally, Jnk2 knockout (Jnk2-/- ), Jnk1Δhepa/2-/- and Mdr2 knockout mice were included. Mice were subjected to bile duct ligation (BDL) for 28 days. Hepatic damage, cell death, proliferation, inflammation and fibrosis were assessed by immunostainings, Western Blot and qRT-PCR. Additionally, microarray analysis and bone marrow transplantation (BMT) were performed.

Results Protein expression of pJNK was significantly increased in human PSC and PBC samples and correlated with disease activity. Furthermore, mice with surgically- or genetically-induced cholestasis (BDL and Mdr2-/- ) showed increased pJNK expression. After BDL, Jnk2∆hepa livers showed no significant differences in hepatic injury, inflammation and fibrosis compared to WT controls. In contrast, Jnk1Δhepa/2Δhepa livers exhibited exacerbated liver damage and immunostainings of liver sections revealed increased cell death, proliferation, inflammation and fibrogenesis demonstrating a combined protective role of Jnk genes in hepatocytes during cholestasis. Moreover, Jnk2-/- and Jnk1Δhepa/2-/- mice displayed increased liver injury and fibrosis compared to Jnk2Δhepa and Jnk1Δhepa/2Δhepa mice, respectively. Finally, BMT experiments demonstrated the involvement of Jnk2 in NPCs but not in BM-derived cells in controlling BDL-dependent disease progression.

Conclusion 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 additional protection during cholestasis. Hence JNKs have a differential and cell-type specific protective role during cholestasis.



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Artikel online veröffentlicht:
04. Januar 2021

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