TY - JOUR
T1 - Depletion of RIPK1 in hepatocytes exacerbates liver damage in fulminant viral hepatitis
AU - Farooq, Muhammad
AU - Filliol, Aveline
AU - Simoes Eugénio, Mélanie
AU - Piquet-Pellorce, Claire
AU - Dion, Sarah
AU - Raguenes-Nicol, Céline
AU - Jan, Aurélien
AU - Dimanche-Boitrel, Marie Thérèse
AU - Le Seyec, Jacques
AU - Samson, Michel
N1 - Funding Information:
For immunohistochemistry analysis, bead-based immunoassays, and animal house facilities, we would like to thank dedicated platforms (i.e. H2P2, flow cytometry and cell sorting, and animal house platforms) of SFR BIOSIT, University of Rennes 1, France. We would also like to thanks Pr. S. Perlman from the University of Iowa for the generous gift of the plasmid pBAC-JHMVIA, Dr. M. Bertrand and Pr. P. Vandenabeele, both from the Inflammation Research Center, VIB (Belgium) for the provision of Ripk1LPC-KO mice. We are grateful to Eoin Mitchell for its technical assistance and English proofreading and to Muhammad Usman for English proofreading. This work was supported by the INSERM (https://www.inserm.fr/en); the University of Rennes 1 (https://www. univ-rennes1.fr/); the “Région Bretagne” (http://www.bretagne.bzh/); the “Ligue Contre le Cancer, Comités du Grand Ouest” (https://www.ligue-cancer.net/); a “Contrat de Plan Etat-Région” (CPER) grant named “Infectio”; and the “Fondation pour la Recherche Médicale” (FRM, https://www.frm.org/). M.F. was supported by a PhD fellowship from the Government of Pakistan (Higher Education Commission). A.F. was supported by a PhD fellowship from the “Région Bretagne”. M.S.E. was supported by a PhD fellowship from “Région Bretagne” and “Ministère de l’Enseignement Supérieur et de la Recherche”.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/1/1
Y1 - 2019/1/1
N2 - The protein kinase RIPK1 plays a crucial role at the crossroad of stress-induced signaling pathways that affects cell’s decision to live or die. The present study aimed to define the role of RIPK1 in hepatocytes during fulminant viral hepatitis, a worldwide syndrome mainly observed in hepatitis B virus (HBV) infected patients. Mice deficient for RIPK1, specifically in liver parenchymal cells (Ripk1 LPC-KO ) and their wild-type littermates (Ripk1 fl/fl ), were challenged by either the murine hepatitis virus type 3 (MHV3) or poly I:C, a synthetic analog of double-stranded RNA mimicking viral pathogen-associated molecular pattern. Ripk1 LPC-KO mice developed more severe symptoms at early stage of the MHV3-induced fulminant hepatitis. Similarly, administration of poly I:C only triggered increase of systemic transaminases in Ripk1 LPC-KO mice, reflecting liver damage through induced apoptosis as illustrated by cleaved-caspase 3 labeling of liver tissue sections. Neutralization of TNF-α or prior depletion of macrophages were able to prevent the appearance of apoptosis of hepatocytes in poly I:C-challenged Ripk1 LPC-KO mice. Moreover, poly I:C never induced direct hepatocyte death in primary culture whatever the murine genotype, while it always stimulated an anti-viral response. Our investigations demonstrated that RIPK1 protects hepatocytes from TNF-α secreted from macrophages during viral induced fulminant hepatitis. These data emphasize the potential worsening risks of an HBV infection in people with polymorphism or homozygous amorphic mutations already described for the RIPK1 gene.
AB - The protein kinase RIPK1 plays a crucial role at the crossroad of stress-induced signaling pathways that affects cell’s decision to live or die. The present study aimed to define the role of RIPK1 in hepatocytes during fulminant viral hepatitis, a worldwide syndrome mainly observed in hepatitis B virus (HBV) infected patients. Mice deficient for RIPK1, specifically in liver parenchymal cells (Ripk1 LPC-KO ) and their wild-type littermates (Ripk1 fl/fl ), were challenged by either the murine hepatitis virus type 3 (MHV3) or poly I:C, a synthetic analog of double-stranded RNA mimicking viral pathogen-associated molecular pattern. Ripk1 LPC-KO mice developed more severe symptoms at early stage of the MHV3-induced fulminant hepatitis. Similarly, administration of poly I:C only triggered increase of systemic transaminases in Ripk1 LPC-KO mice, reflecting liver damage through induced apoptosis as illustrated by cleaved-caspase 3 labeling of liver tissue sections. Neutralization of TNF-α or prior depletion of macrophages were able to prevent the appearance of apoptosis of hepatocytes in poly I:C-challenged Ripk1 LPC-KO mice. Moreover, poly I:C never induced direct hepatocyte death in primary culture whatever the murine genotype, while it always stimulated an anti-viral response. Our investigations demonstrated that RIPK1 protects hepatocytes from TNF-α secreted from macrophages during viral induced fulminant hepatitis. These data emphasize the potential worsening risks of an HBV infection in people with polymorphism or homozygous amorphic mutations already described for the RIPK1 gene.
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UR - http://www.scopus.com/inward/citedby.url?scp=85059785262&partnerID=8YFLogxK
U2 - 10.1038/s41419-018-1277-3
DO - 10.1038/s41419-018-1277-3
M3 - Article
C2 - 30622241
AN - SCOPUS:85059785262
SN - 2041-4889
VL - 10
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 1
M1 - 12
ER -