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RIPK1 protects from TNF-α-mediated liver damage during hepatitis.

ABSTRACT: Cell death of hepatocytes is a prominent characteristic in the pathogenesis of liver disease, while hepatolysis is a starting point of inflammation in hepatitis and loss of hepatic function. However, the precise molecular mechanisms of hepatocyte cell death, the role of the cytokines of hepatic microenvironment and the involvement of intracellular kinases, remain unclear. Tumor necrosis factor alpha (TNF-α) is a key cytokine involved in cell death or survival pathways and the role of RIPK1 has been associated to the TNF-α-dependent signaling pathway. We took advantage of two different deficient mouse lines, the RIPK1 kinase dead knock-in mice (Ripk1^K45A) and the conditional knockout mice lacking RIPK1 only in liver parenchymal cells (Ripk1^LPC-KO), to characterize the role of RIPK1 and TNF-α in hepatitis induced by concanavalin A (ConA). Our results show that RIPK1 is dispensable for liver homeostasis under steady-state conditions but in contrast, RIPK1 kinase activity contributes to caspase-independent cell death induction following ConA injection and RIPK1 also serves as a scaffold, protecting hepatocytes from massive apoptotic cell death in this model. In the Ripk1^LPC-KO mice challenged with ConA, TNF-α triggers apoptosis, responsible for the observed severe hepatitis. Mechanism potentially involves both TNF-independent canonical NF-κB activation, as well as TNF-dependent, but canonical NF-κB-independent mechanisms. In conclusion, our results suggest that RIPK1 kinase activity is a pertinent therapeutic target to protect liver against excessive cell death in liver diseases.

SUBMITTER: Filliol A

PROVIDER: S-EPMC5260888 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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RIPK1 protects from TNF-α-mediated liver damage during hepatitis.

Filliol Aveline A Piquet-Pellorce Claire C Le Seyec Jacques J Farooq Muhammad M Genet Valentine V Lucas-Clerc Catherine C Bertin John J Gough Peter J PJ Dimanche-Boitrel Marie-Thérèse MT Vandenabeele Peter P Bertrand Mathieu Jm MJ Samson Michel M

Cell death & disease 20161110 11

Cell death of hepatocytes is a prominent characteristic in the pathogenesis of liver disease, while hepatolysis is a starting point of inflammation in hepatitis and loss of hepatic function. However, the precise molecular mechanisms of hepatocyte cell death, the role of the cytokines of hepatic microenvironment and the involvement of intracellular kinases, remain unclear. Tumor necrosis factor alpha (TNF-α) is a key cytokine involved in cell death or survival pathways and the role of RIPK1 has b ...[more]

PMID: 27831558

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RIPK1 protects from TNF-α-mediated liver damage during hepatitis.

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RIPK1 protects from TNF-α-mediated liver damage during hepatitis.

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