TY - JOUR
T1 - RIPK1 protects from TNF-α-mediated liver damage during hepatitis
AU - Filliol, Aveline
AU - Piquet-Pellorce, Claire
AU - Le Seyec, Jacques
AU - Farooq, Muhammad
AU - Genet, Valentine
AU - Lucas-Clerc, Catherine
AU - Bertin, John
AU - Gough, Peter J.
AU - Dimanche-Boitrel, Marie Thérèse
AU - Vandenabeele, Peter
AU - Bertrand, Mathieu J.M.
AU - Samson, Michel
N1 - Funding Information:
This work was supported by Inserm, The Ministère de l'Education Nationale de la Recherche et de la Technologie, the University of Rennes 1, the Région Bretagne, the INCa (Institut national du cancer), and the 'Ligue contre le cancer, comités du grand Ouest'. Research in the Vandenabeele group is supported by Belgian grants (Interuniversity Attraction Poles, IAP 7/32), Flemish grants (Research Foundation Flanders: FWO G.0875.11, FWO G.0973.11, FWO G.0A45.12N, FWO G.0172.12, FWO G.0787.13N, FWO G.0607.13N, FWO KAN 31528711, FWO KAN 1504813N, FWO G0E04.16N), Methusalem grant (BOF16/MET-V/007), Ghent University grants (MRP, GROUP-ID consortium, BOFGOA2014000702), grant from the Foundation against Cancer (F94), and grants from VIB. AF was supported by a PhD fellowship from the Région Bretagne. MF was supported by a PhD fellowship from the Government of Pakistan (Higher Education Commission, University of Agriculture, Lahore). PV is senior full professor at Ghent University and holds a Methusalem grant (BOF09/01M00709). For immunohistochemistry analysis and animal house facilities, we would like to thank dedicated platforms (i.e., H2P2 and animal house platforms) of SFR BIOSIT, University of Rennes 1, France. We would also like to thank Barbara Gilbert and Cristina Ulecia Morón for technical assistance.
Publisher Copyright:
© The Author(s) 2016.
PY - 2016/11/10
Y1 - 2016/11/10
N2 - 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-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.
AB - 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-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.
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U2 - 10.1038/cddis.2016.362
DO - 10.1038/cddis.2016.362
M3 - Article
C2 - 27831558
AN - SCOPUS:84995378013
SN - 2041-4889
VL - 7
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 11
M1 - e2462
ER -