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Depletion of RIPK1 in hepatocytes exacerbates liver damage in fulminant viral hepatitis

Abstract : 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 (Ripk1LPC-KO) and their wild-type littermates (Ripk1fl/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. Ripk1LPC-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 Ripk1LPC-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 Ripk1LPC-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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Submitted on : Wednesday, September 30, 2020 - 11:44:46 AM
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Muhammad Farooq, Aveline Filliol, Mélanie Simoes Eugénio, Claire Piquet-Pellorce, Sarah Dion, et al.. Depletion of RIPK1 in hepatocytes exacerbates liver damage in fulminant viral hepatitis. Cell Death and Disease, Nature Publishing Group, 2019, 10 (1), pp.12. ⟨10.1038/s41419-018-1277-3⟩. ⟨hal-01978719⟩

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