Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis
Author(s): ,
Christian Trautwein
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
Corresponding authors. Addresses: Department of Immunology, Ophtalmology and ORL, Complutense University School of Medicine, Plaza de Ramón y Cajal s/n, Madrid 28040, Spain. Tel.: +34 91 394 1385; fax: +34 91 394 1641 (F. Javier Cubero), or Christian Tra
,
Maximilian Hatting
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Christian Liedtke
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Tom Luedde
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Nikolaus Gassler
Affiliations:
Institute of Pathology, Braunschweig Hospital, Braunschweig, Germany
,
Henning W. Zimmermann
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Johanna Reißing
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Astrid Ruiz-Margain
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Ricardo Macías-Rodríguez
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Miguel Eugenio Zoubek
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Gang Zhao
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Huan Su
Affiliations:
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
,
Lijun Liao
Affiliations:
Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji University, Shanghai, China
,
Jin Peng
Affiliations:
Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing Jiangsu, China
Francisco Javier Cubero
Affiliations:
12 de Octubre Health Research Institute (imas12), Madrid, Spain
Corresponding authors. Addresses: Department of Immunology, Ophtalmology and ORL, Complutense University School of Medicine, Plaza de Ramón y Cajal s/n, Madrid 28040, Spain. Tel.: +34 91 394 1385; fax: +34 91 394 1641 (F. Javier Cubero), or Christian Tra
EASL LiverTree™. Trautwein C. Dec 1, 2018; 256742
Prof. Christian Trautwein
Prof. Christian Trautwein
Contributions
Journal Abstract
References
Graphical abstract

Graphical abstract

Overexpression of activated CASP8 and RIPK3 is characteristic of liver biopsies from patients with PBC. Loss of CASP8 in liver parenchymal cells confers protection in experimental cholestasis. Inactivation of CASP8 inhibition does not trigger necroptosis. Pan-caspase inhibition blocked CASP8 but failed to prevent experimental cholestasis.

Background & Aims

Caspase 8 (CASP8) is the apical initiator caspase in death receptor-mediated apoptosis. Strong evidence for a link between death receptor signaling pathways and cholestasis has recently emerged. Herein, we investigated the role of CASP8-dependent and independent pathways during experimental cholestasis.

Methods

Liver injury was characterized in a cohort of human sera (n = 28) and biopsies from patients with stage IV primary biliary cholangitis. In parallel, mice with either specific deletion of Casp8 in liver parenchymal cells (Casp8Δhepa) or hepatocytes (Casp8Δhep), and mice with constitutive Ripk3 (Ripk3−/−) deletion, were subjected to surgical ligation of the common bile duct (BDL) from 2 to 28 days. Floxed (Casp8fl/fl) and Ripk3+/+ mice were used as controls. Moreover, the pan-caspase inhibitor IDN-7314 was used, and cell death mechanisms were studied in primary isolated hepatocytes.

Results

Overexpression of activated caspase 3, CASP8 and RIPK3 was characteristic of liver explants from patients with primary biliary cholangitis. Twenty-eight days after BDL, Casp8Δhepamice showed decreased necrotic foci, serum aminotransferase levels and apoptosis along with diminished compensatory proliferation and ductular reaction. These results correlated with a decreased inflammatory profile and ameliorated liver fibrogenesis. A similar phenotype was observed in Ripk3−/− mice. IDN-7314 treatment decreased CASP8 levels but failed to prevent BDL-induced cholestasis, independently of CASP8 in hepatocytes.

Conclusion

These findings show that intervention against CASP8 in liver parenchymal cells – specifically in cholangiocytes – might be a beneficial option for treating obstructive cholestasis, while broad pan-caspase inhibition might trigger undesirable side effects.

Lay summary

Loss of caspase 8 – a protein involved in programmed cell death – in liver parenchymal cells protects against experimental cholestasis. Therefore, specific pharmacological intervention against caspase 8 might be a valid alternative for the treatment of obstructive cholestasis in the clinic, whereas broad pan-caspase inhibiting drugs might trigger undesirable side effects.

Keyword(s)
Caspase 8, BDL, PBC, Cholestasis, Hepatocytes, Cholangiocytes
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