RIPK1 protects from TNF-α-mediated liver damage during hepatitis.
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 (Ripk1K45A) and the conditional knockout mice lacking RIPK1 only in liver parenchymal cells (Ripk1LPC-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 Ripk1LPC-KOmice 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.
Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France.|Université de Rennes 1, Rennes, France.|Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France.
Aveline
A
Filliol
Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France.|Université de Rennes 1, Rennes, France.|Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France.
Claire
C
Piquet-Pellorce
Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France.|Université de Rennes 1, Rennes, France.|Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France.
Jacques
J
Le Seyec
Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France.|Université de Rennes 1, Rennes, France.|Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France.
Muhammad
M
Farooq
Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France.|Université de Rennes 1, Rennes, France.|Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France.
Valentine
V
Genet
Université de Rennes 1, Rennes, France.|Service de Biochimie CHU Rennes, Université de Rennes 1, Rennes, France.
Catherine
C
Lucas-Clerc
Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA.
John
J
Bertin
Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA.
Peter J
PJ
Gough
Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France.|Université de Rennes 1, Rennes, France.|Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France.
Marie-Thérèse
MT
Dimanche-Boitrel
Inflammation Research Center, VIB, Zwijnaarde-Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Zwijnaarde-Ghent, Belgium.
Peter
P
Vandenabeele
Inflammation Research Center, VIB, Zwijnaarde-Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Zwijnaarde-Ghent, Belgium.
Mathieu Jm
MJ
Bertrand
Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche Santé Environnement et Travail (IRSET), Rennes, France.|Université de Rennes 1, Rennes, France.|Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France.
Michel
M
Samson
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003208:Concanavalin A; D006505:Hepatitis / Q000150:complications / Q000473:pathology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008099:Liver / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D020011:Protective Agents / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects*
D020011:Protective Agents; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse